IL-11调控中子辐射肠上皮细胞损伤的ERK和PI3K/Akt信号转导机制研究
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摘要
目的和意义
中子辐射肠损伤重、难恢复,且目前尚无防治良策。本课题组前期研究发现,IL-11可减轻中子辐射对肠道损伤,促进肠上皮再生,其防治机制与IL-11刺激肠上皮细胞IL-11受体表达上调并激活Jak/STAT信号转导通路有关。但有关IL-11诱导的ERK及PI3K通路在中子辐射肠上皮细胞损伤发生发展中的变化以及通路之间的相互作用、IL-11对Bax和Bcl-2的调节研究尚属空白。在中子辐射诱发的损伤中,多种基因表达的变化可能发挥重要作用,基因芯片技术可高通量地筛选损伤后差异表达基因谱,并为深入探讨IL-11信号转导机制提供线索。为此,本研究对上述问题进行探讨,为阐明中子辐射肠道损伤及IL-11调控的分子机制,并为寻找新的防治措施奠定理论基础。
材料与方法
168只BALB/c二级雄性小鼠,分别经3Gy中子和10Gyγ射线照射,中子照后腹腔注射500μg/kg的rhIL-11,每日1次,连用5 d,于照后6 h、1 d、2 d、3 d和5 d活杀取材。同时采用4Gy中子和10Gyγ射线照射IEC-6细胞,并于照射前12 h或照射后即刻给予100ng/ml的rhIL-11,于rhIL-11处理前12 h分别加入10μM U0126或LY294002。采用基因芯片、RT-PCR、HE染色、MTT、流式细胞术、Hoechst染色、免疫组化、免疫印迹和图像分析等技术,研究中子照射后小鼠空肠组织差异表达基因及肠道病理形态的变化;探讨IL-11及U0126和LY294002对小鼠肠道病理形态、IEC-6细胞增殖活力及凋亡和坏死率的影响以及IEC-6细胞Raf-1、MEK1/2、ERK1/2、PI3K、PDK1、PTEN和Akt表达及活化的影响。
实验结果
1.小鼠死亡情况及小肠病理改变:(1)3Gy中子照射后小鼠于3~5 d内全部死亡,并出现腹泻症状,体重进行性下降;照射后6 h~3 d,肠黏膜大面积坏死脱落,绒毛上皮细胞稀疏、排列紊乱,细胞肿胀;隐窝细胞数量急剧减少,伤后2 d时隐窝中细胞少见、结构破坏,绒毛上皮及基部细胞浆出现嗜酸性变,核浓缩及核碎片形成,照后3 d偶见隐窝细胞再生;IL-11治疗组照后3~5 d小鼠存活曲线右移,腹泻率降低,治疗后3 d隐窝再生较明显,肠绒毛上皮细胞数目较多。
2.小鼠小肠差异表达基因改变:3Gy中子照射后6 h,小鼠空肠组织中存在608个差异表达的基因,其中上调的有277个,下调的有331个,差异基因涉及细胞的增殖与凋亡、MAPK和PI3K/Akt等多条信号通路等。
3. IEC-6细胞生物学行为的改变:(1)10Gyγ射线照射后6 h,IEC-6细胞凋亡和坏死率增加、增殖活力下降、细胞周期阻滞;IL-11处理组凋亡和坏死率下降。(2)4Gy中子照射后6 h,IEC-6细胞肿胀变圆、凋亡和坏死率增加、增殖活力下降;照射后24 h,IEC-6细胞凋亡和坏死率无明显变化,增殖活力下降。IL-11处理组,其形态较好、增殖活力升高、凋亡和坏死率下降。
4. IEC-6细胞ERK信号通路的改变及U0126对其生物学行为影响:(1)10Gyγ射线照射后6~24h,IEC-6细胞Raf-1表达和活化及MEK1/2活化升高,ERK1/2活化减弱;与照射组比较,IL-11处理组于照射后5~15min可增加Raf-1和MEK1/2活性,其余时间点改变不明显,照射后6 h抑制ERK1/2活化。(2)4Gy中子照后6~24 h,Raf-1表达和活化及MEK1/2活化无明显变化,ERK1/2表达和活化升高;与照射组比较,IL-11处理组照后6 h,Raf-1表达变化不明显,照后6~24 h,MEK1/2活化升高,IL-11在照后6 h抑制ERK1/2表达及活化,照后24 h增加ERK1/2表达及活化。(3)IL-11处理前应用U0126处理IEC-6细胞,4Gy中子照射后6~24 h,其增殖活力较IL-11处理组下降,凋亡和坏死率变化不明显。
5. IEC-6细胞PI3K/Akt信号通路的改变及LY294002对其生物学行为影响:(1)10Gyγ射线照射后6 h,IEC-6细胞PI3K表达和Akt活化减弱,Akt表达、PDK1及PTEN活化增加;IL-11处理组PI3K表达和Akt活化增加,Akt表达、PDK1及PTEN活化减弱。(2)4Gy中子照后6 h,IEC-6细胞PI3K表达减少,24 h恢复;照后6~24 h,PDK1及PTEN活化增加,Akt活化减弱;IL-11处理组照后6~24 h,PI3K表达和Akt活化增强,PDK1和PTEN活化减弱。(3)IL-11处理前应用LY294002处理IEC-6细胞,4Gy中子照射后6~24 h,其增殖活力较IL-11处理组下降,凋亡和坏死率变化增加。
6. ERK和PI3K/Akt信号通路间的相互调控:(1)U0126处理组IEC-6细胞在照后6~24 h,ERK1/2表达和活化较IL-11处理组无明显变化,但PDK1及Akt活化均增加。(2)LY294002处理组IEC-6细胞与IL-11处理组比较,照后6~24 h,Akt活化及ERK1/2的表达和活化均下降。
7.小鼠小肠Bax和Bcl-2表达的改变:(1)Bax于正常小鼠小肠绒毛上皮细胞呈颗粒状阳性,于隐窝细胞呈弱阳性;3Gy中子和10Gyγ线照射后6 h~3 d,Bax表达显著增强;3Gy中子照射后应用IL-11治疗,Bax表达于照后3 d减弱。(2)Bcl-2于正常小鼠肠绒毛和隐窝细胞浆呈弱阳性表达;3Gy中子照射后6 h~3d,Bcl-2表达无明显变化;10Gyγ线照射后6 h~3 d,Bcl-2表达升高;3Gy中子照射后应用IL-11治疗,Bcl-2表达于照后3 d升高。
结论
1.中子照射可致小鼠空肠多靶点的损伤,涉及包括PI3K/Akt和MAPK在内的多条通路。
2.中子照射后肠上皮细胞内ERK1/2持续激活,IL-11对其活化呈先抑制后激活的波动趋势,提示ERK在中子辐射肠上皮细胞损伤与修复的不同阶段发挥不同的作用。
3.中子照射时,PI3K/Akt通路活化受抑制,IL-11可通过促进其激活发挥细胞保护作用。
4.中子和γ射线对肠上皮细胞ERK和PI3K/Akt的影响不同,可能是二者致伤差异的分子机制。
5. IL-11调控中子辐射肠上皮细胞时,ERK和PI3K/Akt通路在IEC-6细胞内可能通过一个反馈环路联系:ERK1/2的持续激活反馈性抑制了PI3K/Akt的活性,IL-11对ERK的抑制作用,则协同IL-11促进了PI3K/Akt途径活性的上调;ERK1/2的活性受PI3K的调节而不依赖于MEK1/2。
6.在中子辐射时,LY294002阻断IL-11对肠上皮细胞的保护作用较U0126更显著,提示ERK和PI3K/Akt通路在介导IL-11保护作用中地位不同,ERK主要与细胞的增殖有关,而PI3K/Akt则与细胞的增殖与死亡反应均有关。
7.中子辐射肠道损伤时,IL-11可通过减小Bax/Bcl-2比值发挥保护作用。
AIMS AND SIGNIFICANCE
Neutron radiation can cause severe damages to the intestine which is hard to recover. Unfortunately, there is still no good cure so far. Our previous study showed that IL-11 could attenuate the intestinal injury and promote recovery of intestinal epithelium. And the protection mechanism of IL-11 was related to the up-regulations of the IL-11 receptors and Jak/STAT activation. But it’s still unknown whether ERK and PI3K/Akt signaling pathways induced by IL-11 are involved in the intestinal injury and recovery after neutron irradiation. How do the ERK and PI3K/Akt signaling pathways interact in these processes? Are Bax and Bcl-2 attributed to the cytoprotection of IL-11? All the three questions remain to be answered. In addition, various genes may play a role in the regulation of radiation response of the intestine. Gene chip makes it come true to screening out differentially expressed genomics in a high-flux way and the results maybe offer helpful clues to the next exploration of IL-11 signaling. Therefore, in this study we investigated the above topics and sought to elucidate the molecular mechanism of IL-11 regulation in neutron irradiation-induced intestinal injury, which might help to find new potential therapies.
MATERIAS AND METHODS
168 BALB/c mice were irradiated by 3 Gy neutron or 10 Gyγirradiation and injected with rhIL-11 at a dose of 500μg/kg body weight once per day for 5 days after irradiation. The mice were sacrificed at 6 h, 1d, 2d, 3d and 5d after irradiation. IEC-6 cells were exposed to 4 Gy neutron or 10 Gyγirradiation and treated with 100ng/ml rhIL-11 12 h prior to or immediately after irradiation. 10μM U0126 or LY294002 was added 12 h prior to IL-11 treatment. Gene chip, RT-PCR, HE staining, MTT, flow cytometry, Hoechst staining, immunohistochemistry, Western Blot and image analysis were used to detect the differentially expressed genes, histopathological changes in the mouse jejunum and determine the effect of IL-11, Uo126 and LY294002 on the intestinal pathology, IEC-6 cellular biological behaviors and expressions and activities of Raf-1, MEK1/2, ERK1/2, PI3K, PDK1, PTEN and Akt.
RESULTS
1. Survival and intestinal histological changes in the mice: (1) All of the mice received 3 Gy neutron irradiation died in 3~5 d after irradiation; and diarrhea occurred in every irradiated mice and the body weight lost rapidly and progressively. The small intestinal mucosa of the neutron irradiated mice showed marked destruction with villus epithelium decrease, disorder and swelling; cryptal cell number decreased sharply and the crypts were destructed with rare cell number at the 2nd d. The epithelia cells showed acidophily, pyknosis and karuorrhexis. Regeneration was rare at 3d. The mice with IL-11 administration showed significant increase in survival fraction, decrease in diarrhea, more crypt regeneration and villous cells.
2. Differentially expressed genes in the murine small intestine: After 6 h of 3 Gy neutron irradiation, there were 608 genes differentially expressed in the small intestine, of which 277 genes were up-regulated and 331 genes were down-regulated. The differentially expressed genes were related to cellular proliferation and apoptosis, MAPK, PI3K/Akt signaling and so on.
3. Changes of IEC-6 cellular biological behaviors: (1) At 6 h after 10 Gyγirradiation, IEC-6 cells showed higher rates of apoptosis and necrosis, lower proliferating capability and cell cycle arrest. IL-11 treatment down-regulated the rate of apoptosis and necrosis. (2) At 6 h after 4 Gy neutron irradiation, IEC-6 cells became round in shape and showed higher rates of apoptosis and necrosis and lower proliferating capability; at 24 h after neutron irradiation, the rates of apoptosis and necrosis showed no marked changes but the proliferating capability was still lower than normal. IL-11-treated IEC-6 cells showed better in morphology, lower apoptosis rate and stronger proliferating capability.
4. Changes of ERK pathway in IEC-6 cells and effect of U0126 on IEC-6 cellular biological behaviors: (1) The expression and activity of Raf-1 and MEK1/2 increased but ERK1/2 activation decreased in 6~24 h after 10 Gyγirradiation. IL-11 increased the activities of Raf-1 and MEK1/2 in 5~15min and inhibited ERK1/2 activity at 6 h after radiation. (2) The expression and activity of Raf-1 and MEK1/2 showed no significant changes in 6~24 h after 4 Gy neutron irradiation while the expression and activity of ERK1/2 increased. IL-11 treatment didn’t change the expression of Raf-1 at 6 h and increased the activity of MEK1/2 in 6~24 h. As well as the expression and activity of ERK1/2 was concerned, IL-11 functioned as inhition at 6 h and promotion at 24 h. (3) Compared with IL-11 treated IEC-6 cells, cells with U0126 added before IL-11 showed lower proliferating capability but no obvious changed in cell death at 6 and 24 h after 4 Gy neutron irradiation.
5. Changes of PI3K/Akt pathway in IEC-6 cells and effect of LY294002 on IEC-6 cellular biological behaviors: (1) At 6 h after 10 Gyγirradiation, the expression of PI3K and activation of Akt in IEC-6 cells decreased while the expression of Akt, activities of PDK1 and PTEN increased. IL-11 treatment increased the expression of PI3K and activation of Akt and decreased the expression of Akt, activities of PDK1 and PTEN. (2) After 4 Gy neutron irradiation, the expression of PI3K decreased at 6 h and recovered at 24 h. The activation of PDK1 and PTEN increased, meanwhile the activation of Akt decreased in 6~24 h. IL-11 up-regulated the expression of PI3K and activation of Akt and down-regualted the activation of PDK1 and PTEN. (3) Compared with IL-11 treated IEC-6 cells, cells with LY294002 added before IL-11 showed lower proliferating capability and higher apoptosis and necrosis rate at 6 and 24 h after 4 Gy neutron irradiation.
6. Interactions between ERK and PI3K/Akt pathway: (1) Compared with IL-11 treated IEC-6 cells, U0126 brought no significant changes to the expression and activities of ERK1/2 but increased the activations of PDK1and Akt in 6~24 h after neutron irradiation. (2) Compared with IL-11 treated IEC-6 cells, LY294002 decreased the activations of both Akt and ERK1/2 in 6~24 h after neutron irradiation.
8. Expressions of Bax and Bcl-2 in the murine small intestine: (1) Immunoreactivity of Bax was granulo-positive in the normal small intestinal villous cytoplasm and weakly positive in the cryptal cytoplasm. After 3 Gy neutron and 10Gyγirradiation, Bax immunoreactivity increased greatly in 6 h~3 d. IL-11 adminstration decreased the expression of Bax at 3 d after 3 Gy neutron irradiation. (2) Immunoreactivity of Bax was weakly positive in the normal small intestinal villous and cryptal cytoplasm. 3 Gy neutron brought no changes to the expression of Bcl-2 in 6 h~3 d. 10Gyγirradiation increased the expression of Bcl-2 in 6 h~3 d.
CONCLUSIONS
1. Neutron irradiation resulted in injuries to many molecular targets, involved multi pathway like PI3K/Akt and MAPK in the jejunum.
2. In IEC-6, ERK1/2 was continuously activated by neutron irradiation. The effect of IL-11 on ERK1/2 activation fluctuated from inhibition to promotion. This suggests ERK played dual roles in different stages of neutron-induced IEC injury.
3. PI3K/Akt pathway was inhibited by neutron irradiation and triggered by IL-11 to protect IEC from neutron injury.
4. Neutron andγirradiation had different impacts on ERK and PI3K/Akt pathway, which might underlie their different injury response.
5. There maybe a feedback loop to connect ERK and PI3K/Akt pathway when IL-11 regulated neutron induced intestinal epithelial injury: (1) Continuously activated ERK1/2 inhibited PI3K/Akt activity, while ERK inhibition synergized with IL-11 to promote PI3K/Akt activation; (2) The activity of ERK1/2 was regulated by PI3K and independent on MEK1/2.
6. LY294002 was more effective than U0126 to block IL-11 protection the intestinal epithelium from neutron irradiation. This suggests that ERK and PI3K/Akt signaling played different roles in mediating the cytoprotection by IL-11: ERK was mainly associated to cellular proliferation and PI3K/Akt was involved both cellular proliferation and death.
7. IL-11 decreased the ratio of Bax/Bcl-2 to confer protection on the intestine exposed to neutron irradiation.
中子辐射肠损伤重、难恢复,且目前尚无防治良策。本课题组前期研究发现,IL-11可减轻中子辐射对肠道损伤,促进肠上皮再生,其防治机制与IL-11刺激肠上皮细胞IL-11受体表达上调并激活Jak/STAT信号转导通路有关。但有关IL-11诱导的ERK及PI3K通路在中子辐射肠上皮细胞损伤发生发展中的变化以及通路之间的相互作用、IL-11对Bax和Bcl-2的调节研究尚属空白。在中子辐射诱发的损伤中,多种基因表达的变化可能发挥重要作用,基因芯片技术可高通量地筛选损伤后差异表达基因谱,并为深入探讨IL-11信号转导机制提供线索。为此,本研究对上述问题进行探讨,为阐明中子辐射肠道损伤及IL-11调控的分子机制,并为寻找新的防治措施奠定理论基础。
材料与方法
168只BALB/c二级雄性小鼠,分别经3Gy中子和10Gyγ射线照射,中子照后腹腔注射500μg/kg的rhIL-11,每日1次,连用5 d,于照后6 h、1 d、2 d、3 d和5 d活杀取材。同时采用4Gy中子和10Gyγ射线照射IEC-6细胞,并于照射前12 h或照射后即刻给予100ng/ml的rhIL-11,于rhIL-11处理前12 h分别加入10μM U0126或LY294002。采用基因芯片、RT-PCR、HE染色、MTT、流式细胞术、Hoechst染色、免疫组化、免疫印迹和图像分析等技术,研究中子照射后小鼠空肠组织差异表达基因及肠道病理形态的变化;探讨IL-11及U0126和LY294002对小鼠肠道病理形态、IEC-6细胞增殖活力及凋亡和坏死率的影响以及IEC-6细胞Raf-1、MEK1/2、ERK1/2、PI3K、PDK1、PTEN和Akt表达及活化的影响。
实验结果
1.小鼠死亡情况及小肠病理改变:(1)3Gy中子照射后小鼠于3~5 d内全部死亡,并出现腹泻症状,体重进行性下降;照射后6 h~3 d,肠黏膜大面积坏死脱落,绒毛上皮细胞稀疏、排列紊乱,细胞肿胀;隐窝细胞数量急剧减少,伤后2 d时隐窝中细胞少见、结构破坏,绒毛上皮及基部细胞浆出现嗜酸性变,核浓缩及核碎片形成,照后3 d偶见隐窝细胞再生;IL-11治疗组照后3~5 d小鼠存活曲线右移,腹泻率降低,治疗后3 d隐窝再生较明显,肠绒毛上皮细胞数目较多。
2.小鼠小肠差异表达基因改变:3Gy中子照射后6 h,小鼠空肠组织中存在608个差异表达的基因,其中上调的有277个,下调的有331个,差异基因涉及细胞的增殖与凋亡、MAPK和PI3K/Akt等多条信号通路等。
3. IEC-6细胞生物学行为的改变:(1)10Gyγ射线照射后6 h,IEC-6细胞凋亡和坏死率增加、增殖活力下降、细胞周期阻滞;IL-11处理组凋亡和坏死率下降。(2)4Gy中子照射后6 h,IEC-6细胞肿胀变圆、凋亡和坏死率增加、增殖活力下降;照射后24 h,IEC-6细胞凋亡和坏死率无明显变化,增殖活力下降。IL-11处理组,其形态较好、增殖活力升高、凋亡和坏死率下降。
4. IEC-6细胞ERK信号通路的改变及U0126对其生物学行为影响:(1)10Gyγ射线照射后6~24h,IEC-6细胞Raf-1表达和活化及MEK1/2活化升高,ERK1/2活化减弱;与照射组比较,IL-11处理组于照射后5~15min可增加Raf-1和MEK1/2活性,其余时间点改变不明显,照射后6 h抑制ERK1/2活化。(2)4Gy中子照后6~24 h,Raf-1表达和活化及MEK1/2活化无明显变化,ERK1/2表达和活化升高;与照射组比较,IL-11处理组照后6 h,Raf-1表达变化不明显,照后6~24 h,MEK1/2活化升高,IL-11在照后6 h抑制ERK1/2表达及活化,照后24 h增加ERK1/2表达及活化。(3)IL-11处理前应用U0126处理IEC-6细胞,4Gy中子照射后6~24 h,其增殖活力较IL-11处理组下降,凋亡和坏死率变化不明显。
5. IEC-6细胞PI3K/Akt信号通路的改变及LY294002对其生物学行为影响:(1)10Gyγ射线照射后6 h,IEC-6细胞PI3K表达和Akt活化减弱,Akt表达、PDK1及PTEN活化增加;IL-11处理组PI3K表达和Akt活化增加,Akt表达、PDK1及PTEN活化减弱。(2)4Gy中子照后6 h,IEC-6细胞PI3K表达减少,24 h恢复;照后6~24 h,PDK1及PTEN活化增加,Akt活化减弱;IL-11处理组照后6~24 h,PI3K表达和Akt活化增强,PDK1和PTEN活化减弱。(3)IL-11处理前应用LY294002处理IEC-6细胞,4Gy中子照射后6~24 h,其增殖活力较IL-11处理组下降,凋亡和坏死率变化增加。
6. ERK和PI3K/Akt信号通路间的相互调控:(1)U0126处理组IEC-6细胞在照后6~24 h,ERK1/2表达和活化较IL-11处理组无明显变化,但PDK1及Akt活化均增加。(2)LY294002处理组IEC-6细胞与IL-11处理组比较,照后6~24 h,Akt活化及ERK1/2的表达和活化均下降。
7.小鼠小肠Bax和Bcl-2表达的改变:(1)Bax于正常小鼠小肠绒毛上皮细胞呈颗粒状阳性,于隐窝细胞呈弱阳性;3Gy中子和10Gyγ线照射后6 h~3 d,Bax表达显著增强;3Gy中子照射后应用IL-11治疗,Bax表达于照后3 d减弱。(2)Bcl-2于正常小鼠肠绒毛和隐窝细胞浆呈弱阳性表达;3Gy中子照射后6 h~3d,Bcl-2表达无明显变化;10Gyγ线照射后6 h~3 d,Bcl-2表达升高;3Gy中子照射后应用IL-11治疗,Bcl-2表达于照后3 d升高。
结论
1.中子照射可致小鼠空肠多靶点的损伤,涉及包括PI3K/Akt和MAPK在内的多条通路。
2.中子照射后肠上皮细胞内ERK1/2持续激活,IL-11对其活化呈先抑制后激活的波动趋势,提示ERK在中子辐射肠上皮细胞损伤与修复的不同阶段发挥不同的作用。
3.中子照射时,PI3K/Akt通路活化受抑制,IL-11可通过促进其激活发挥细胞保护作用。
4.中子和γ射线对肠上皮细胞ERK和PI3K/Akt的影响不同,可能是二者致伤差异的分子机制。
5. IL-11调控中子辐射肠上皮细胞时,ERK和PI3K/Akt通路在IEC-6细胞内可能通过一个反馈环路联系:ERK1/2的持续激活反馈性抑制了PI3K/Akt的活性,IL-11对ERK的抑制作用,则协同IL-11促进了PI3K/Akt途径活性的上调;ERK1/2的活性受PI3K的调节而不依赖于MEK1/2。
6.在中子辐射时,LY294002阻断IL-11对肠上皮细胞的保护作用较U0126更显著,提示ERK和PI3K/Akt通路在介导IL-11保护作用中地位不同,ERK主要与细胞的增殖有关,而PI3K/Akt则与细胞的增殖与死亡反应均有关。
7.中子辐射肠道损伤时,IL-11可通过减小Bax/Bcl-2比值发挥保护作用。
AIMS AND SIGNIFICANCE
Neutron radiation can cause severe damages to the intestine which is hard to recover. Unfortunately, there is still no good cure so far. Our previous study showed that IL-11 could attenuate the intestinal injury and promote recovery of intestinal epithelium. And the protection mechanism of IL-11 was related to the up-regulations of the IL-11 receptors and Jak/STAT activation. But it’s still unknown whether ERK and PI3K/Akt signaling pathways induced by IL-11 are involved in the intestinal injury and recovery after neutron irradiation. How do the ERK and PI3K/Akt signaling pathways interact in these processes? Are Bax and Bcl-2 attributed to the cytoprotection of IL-11? All the three questions remain to be answered. In addition, various genes may play a role in the regulation of radiation response of the intestine. Gene chip makes it come true to screening out differentially expressed genomics in a high-flux way and the results maybe offer helpful clues to the next exploration of IL-11 signaling. Therefore, in this study we investigated the above topics and sought to elucidate the molecular mechanism of IL-11 regulation in neutron irradiation-induced intestinal injury, which might help to find new potential therapies.
MATERIAS AND METHODS
168 BALB/c mice were irradiated by 3 Gy neutron or 10 Gyγirradiation and injected with rhIL-11 at a dose of 500μg/kg body weight once per day for 5 days after irradiation. The mice were sacrificed at 6 h, 1d, 2d, 3d and 5d after irradiation. IEC-6 cells were exposed to 4 Gy neutron or 10 Gyγirradiation and treated with 100ng/ml rhIL-11 12 h prior to or immediately after irradiation. 10μM U0126 or LY294002 was added 12 h prior to IL-11 treatment. Gene chip, RT-PCR, HE staining, MTT, flow cytometry, Hoechst staining, immunohistochemistry, Western Blot and image analysis were used to detect the differentially expressed genes, histopathological changes in the mouse jejunum and determine the effect of IL-11, Uo126 and LY294002 on the intestinal pathology, IEC-6 cellular biological behaviors and expressions and activities of Raf-1, MEK1/2, ERK1/2, PI3K, PDK1, PTEN and Akt.
RESULTS
1. Survival and intestinal histological changes in the mice: (1) All of the mice received 3 Gy neutron irradiation died in 3~5 d after irradiation; and diarrhea occurred in every irradiated mice and the body weight lost rapidly and progressively. The small intestinal mucosa of the neutron irradiated mice showed marked destruction with villus epithelium decrease, disorder and swelling; cryptal cell number decreased sharply and the crypts were destructed with rare cell number at the 2nd d. The epithelia cells showed acidophily, pyknosis and karuorrhexis. Regeneration was rare at 3d. The mice with IL-11 administration showed significant increase in survival fraction, decrease in diarrhea, more crypt regeneration and villous cells.
2. Differentially expressed genes in the murine small intestine: After 6 h of 3 Gy neutron irradiation, there were 608 genes differentially expressed in the small intestine, of which 277 genes were up-regulated and 331 genes were down-regulated. The differentially expressed genes were related to cellular proliferation and apoptosis, MAPK, PI3K/Akt signaling and so on.
3. Changes of IEC-6 cellular biological behaviors: (1) At 6 h after 10 Gyγirradiation, IEC-6 cells showed higher rates of apoptosis and necrosis, lower proliferating capability and cell cycle arrest. IL-11 treatment down-regulated the rate of apoptosis and necrosis. (2) At 6 h after 4 Gy neutron irradiation, IEC-6 cells became round in shape and showed higher rates of apoptosis and necrosis and lower proliferating capability; at 24 h after neutron irradiation, the rates of apoptosis and necrosis showed no marked changes but the proliferating capability was still lower than normal. IL-11-treated IEC-6 cells showed better in morphology, lower apoptosis rate and stronger proliferating capability.
4. Changes of ERK pathway in IEC-6 cells and effect of U0126 on IEC-6 cellular biological behaviors: (1) The expression and activity of Raf-1 and MEK1/2 increased but ERK1/2 activation decreased in 6~24 h after 10 Gyγirradiation. IL-11 increased the activities of Raf-1 and MEK1/2 in 5~15min and inhibited ERK1/2 activity at 6 h after radiation. (2) The expression and activity of Raf-1 and MEK1/2 showed no significant changes in 6~24 h after 4 Gy neutron irradiation while the expression and activity of ERK1/2 increased. IL-11 treatment didn’t change the expression of Raf-1 at 6 h and increased the activity of MEK1/2 in 6~24 h. As well as the expression and activity of ERK1/2 was concerned, IL-11 functioned as inhition at 6 h and promotion at 24 h. (3) Compared with IL-11 treated IEC-6 cells, cells with U0126 added before IL-11 showed lower proliferating capability but no obvious changed in cell death at 6 and 24 h after 4 Gy neutron irradiation.
5. Changes of PI3K/Akt pathway in IEC-6 cells and effect of LY294002 on IEC-6 cellular biological behaviors: (1) At 6 h after 10 Gyγirradiation, the expression of PI3K and activation of Akt in IEC-6 cells decreased while the expression of Akt, activities of PDK1 and PTEN increased. IL-11 treatment increased the expression of PI3K and activation of Akt and decreased the expression of Akt, activities of PDK1 and PTEN. (2) After 4 Gy neutron irradiation, the expression of PI3K decreased at 6 h and recovered at 24 h. The activation of PDK1 and PTEN increased, meanwhile the activation of Akt decreased in 6~24 h. IL-11 up-regulated the expression of PI3K and activation of Akt and down-regualted the activation of PDK1 and PTEN. (3) Compared with IL-11 treated IEC-6 cells, cells with LY294002 added before IL-11 showed lower proliferating capability and higher apoptosis and necrosis rate at 6 and 24 h after 4 Gy neutron irradiation.
6. Interactions between ERK and PI3K/Akt pathway: (1) Compared with IL-11 treated IEC-6 cells, U0126 brought no significant changes to the expression and activities of ERK1/2 but increased the activations of PDK1and Akt in 6~24 h after neutron irradiation. (2) Compared with IL-11 treated IEC-6 cells, LY294002 decreased the activations of both Akt and ERK1/2 in 6~24 h after neutron irradiation.
8. Expressions of Bax and Bcl-2 in the murine small intestine: (1) Immunoreactivity of Bax was granulo-positive in the normal small intestinal villous cytoplasm and weakly positive in the cryptal cytoplasm. After 3 Gy neutron and 10Gyγirradiation, Bax immunoreactivity increased greatly in 6 h~3 d. IL-11 adminstration decreased the expression of Bax at 3 d after 3 Gy neutron irradiation. (2) Immunoreactivity of Bax was weakly positive in the normal small intestinal villous and cryptal cytoplasm. 3 Gy neutron brought no changes to the expression of Bcl-2 in 6 h~3 d. 10Gyγirradiation increased the expression of Bcl-2 in 6 h~3 d.
CONCLUSIONS
1. Neutron irradiation resulted in injuries to many molecular targets, involved multi pathway like PI3K/Akt and MAPK in the jejunum.
2. In IEC-6, ERK1/2 was continuously activated by neutron irradiation. The effect of IL-11 on ERK1/2 activation fluctuated from inhibition to promotion. This suggests ERK played dual roles in different stages of neutron-induced IEC injury.
3. PI3K/Akt pathway was inhibited by neutron irradiation and triggered by IL-11 to protect IEC from neutron injury.
4. Neutron andγirradiation had different impacts on ERK and PI3K/Akt pathway, which might underlie their different injury response.
5. There maybe a feedback loop to connect ERK and PI3K/Akt pathway when IL-11 regulated neutron induced intestinal epithelial injury: (1) Continuously activated ERK1/2 inhibited PI3K/Akt activity, while ERK inhibition synergized with IL-11 to promote PI3K/Akt activation; (2) The activity of ERK1/2 was regulated by PI3K and independent on MEK1/2.
6. LY294002 was more effective than U0126 to block IL-11 protection the intestinal epithelium from neutron irradiation. This suggests that ERK and PI3K/Akt signaling played different roles in mediating the cytoprotection by IL-11: ERK was mainly associated to cellular proliferation and PI3K/Akt was involved both cellular proliferation and death.
7. IL-11 decreased the ratio of Bax/Bcl-2 to confer protection on the intestine exposed to neutron irradiation.
引文
1.候友贤主编.肿瘤放疗治疗学.人民军医出版社,第一版, 2008. 1-5.
2.马林,周桂霞,冯林春主编.恶性肿瘤高LET(重离子、快中子)放射治疗学.军事医学科学出版社,第一版, 2007. 133-135.
3.毛志达.快中子治疗肿瘤的临床进展.癌症, 1998, 17(1): 71-74.
4. Yeoh AS, Gibson RJ, Yeoh EE, et al. A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappa B, COX-1 and COX-2. Mol Cancer Ther, 2007, 6(8):2319-2327.
5. Coopersmith CM, Gordon JI. gamma-ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53. Oncogene, 1997, 15(2):131-141.
6.毛秉智,陈家佩主编.急性放射病基础与临床.军事医学科学出版社,第一版, 2002, 101-131.
7.王宝勤,王珏,谭洪玲,等.细胞因子对中子和γ射线照射小鼠的辐射防护作用及作用机理研究.中华放射医学与防护杂志, 1997, 17(6): 404-407.
8. Butturini A, De Souza PC, Gale RP. Use of recombinant granulocyte-macrophage colony stimulating factor in the Brazil radiation accident. Lancet, 1988, 2(8609):1447-1475.
9. Brandao CE, Oliveira AR, Valverde NJ , et al. Clinical and hematological aspects of 137Cs: the Go iania radiation accident. Health Phys, 1991, 60(1): 31-39.
10.郝静,罗庆良,熊国林,等. rhIL-11不同时间给药对急性放射病猕猴造血系统的影响.中华放射医学与防护杂志, 2001, 21(1):31-34.
11.高亚杰,孙红,乔京京,等.重组人白细胞介素-11对化疗后血小板减少症的治疗作用.中国新药与临床杂志, 2003, 22(5):266-268.
12.王瑞娟,彭瑞云.白介素-11在放射性肠道损伤中的作用研究.中华放射医学与防护杂志, 2005, 25(5): 494-496.
13. Kuenzler KA, Pearson PY, Schwartz MZ. IL-11 pretreatment reduces cell death after intestinal ischemia-reperfusion. J Surg Res, 2002, 108(2):268-272.
14. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11): 10304-10315.
15. Alavi K, Prasad R, Lundgren K, et al. Interleukin-11 enhances small intestine absorptive function and mucosal mass after intestinal adaptation. J Pediatr Surg, 2000, 35(2):371-374.
16. Potten CS. Interleukin-11 protects the clonogenic stem cells in murine small-intestine crypts from impairment of their reproductive capacity by radiation. Int J Cancer, 1995, 62(3): 356-361.
17. Barton VA, Hall MA, Hudson KR, et al. Interleukin-11 signals through the formation of a hexameric receptor complex. J Biol Chem, 2000, 275(46):36197-36203.
18. Du X, Williams DA. Interleukin-11: review of molecular, cell biology and clinical use. Blood, 1997, 89(11):3897-3908.
19. Tenney R, Stansfield K, Pekala PH. Interleukin 11 signaling in 3T3-L1 adipocytes. J Cell Physiol, 2005, 202(1):160-166.
20. Rajgopal R, Butcher M, Weitz JI, et al. Heparin synergistically enhances interleukin-11 signaling through up-regulation of the MAPK pathway. J Biol Chem, 2006, 281(30): 20780-20787.
21. Wang XY, Fuhrer DK, Marshall MS, et al. Interleukin-11 Induces Complex Formation of Grb2, Fyn, and JAK2 in 3T3L1 Cells. J Biol Chem, 1995, 270(47): 27999-28002.
22.朱婉儿,胡长春,谢文婷,等.慢性应激对大鼠海马Akt/FKHR1信号通路活性的影响.心理学报, 2007, 39(4):656-661.
23.张蒙,甘华田. PI3K/AKT信号传导通路与肠道炎症.华西医学, 2006, 21(1): 192-193.
24. Tebbutt NC, Giraud AS, Inglese M,et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med, 2002, 8(10):1089-1097.
25. Naka T, Kishimoto T. Joint disease caused by defective gp130-mediated STAT signaling. Arthritis Res, 2002, 4(3):154-156.
26. Ernst M, Inglese M, Waring P, et al. Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med, 2001, 194(2):189-203.
27. Musso A, Dentelli P, Carlino A, et al. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis, 2005, 11(2):91-98.
28. Mudter J, Weigmann B, Bartsch B, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol, 2005, 100(1):64-72.
29. Alonzi T, Newton IP, Bryce PJ, et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine, 2004, 26(2):45-56.
30. Mogila V, Xia F, Li WX. An intrinsic cell cycle checkpoint pathway mediated by MEK and ERK in Drosophila. Dev Cell, 2006, 11(4):575-582.
31. Kumar P, Coltas IK, Kumar B, et al. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
32. Yacoub A, Park JS, Qiao L, et al. MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 2001, 77(10):1067-1078.
33. Golding SE, Rosenberg E, Neill S, et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res, 2007, 67(3):1046-1053.
34. Kim CS, Kim JK, Nam SY, et al. Low-dose radiation stimulates the proliferation of normal human lung fibroblasts via a transient activation of Raf and Akt. Mol Cells, 2007, 24(3):424-430.
35. Sheng H, Shao J, Townsend CM, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
36. Marino M, Acconcia F, Trentalance A. Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell, 2003, 14(6):2583-2591.
37. Bradley EW, Ruan MM, Vrable A, et al. Pathway crosstalk between Ras/Raf and PI3K in promotion of M-CSF-induced MEK/ERK-mediated osteoclast survival. J Cell Biochem, 2008, 104(4):1439-1451.
38. Shelton JG, Steelman LS, White ER, et al. Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle, 2004, 3(3):372-379.
39. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2):189-218.
40. Wang RJ, Peng RY, Fu KF, et al. Effect of recombinant human interleukin-11 on expressions of interleukin-11 receptorα-chain and glycoprotein 130 in intestinal epithelium cell line-6 after neutron irradiation. World J Gastroenterol, 2006, 12(19): 3055-3059.
41.王瑞娟,彭瑞云,高亚兵,等. IL-11保护中子照射后肠上皮损伤的Jak/STAT信号转导机制研究.细胞与分子免疫学杂志, 2009, 25(1): 27-30.
42.王瑞娟,彭瑞云,韩瑞刚,等. IL-11对中子辐射肠道损伤保护作用的定量病理研究.中国体视学与图像分析, 2006, 11(2): 139-143.
1.毛秉智,陈家佩,主编.急性放射病基础与临床.军事医学科学出版社,第一版, 2002. 102-105.
2.蔡文琴,王伯云编著.实用免疫细胞化学与核酸分子杂交技术.四川科学技术出版社,第一版, 1994: 72-89.
3.毛秉智,陈家佩,主编.急性放射病基础与临床.军事医学科学出版社, 2002. 163-197.
4.罗庆良,从玉文,郝静,等.造血因子与急性放射病.解放军医学杂志, 2005, 30(3): 186-190.
5.吕秋军,高月.白介素11抗辐射损伤作用的研究进展.中华放射医学与防护杂志, 2000, 20(5): 369-370.
6. Frasca D, Guidi F, Arbitrio M, et al. Use of hematopoietic cytokines to accelerate the recovery of the immune system in irradiated mice. Exp Hematol, 1997, 25(11):1167-1171.
7. Shroff EH, Snyder C, Chandel NS. Role of Bcl-2 family members in anoxia induced cell death. Cell Cycle, 2007, 6(7): 807-809.
8.刘玲玉,孟玉强,杨学冬.热休克蛋白生物学作用的研究进展.阴山学刊, 2007, 21(1): 61-64.
9.马旭,吕刚. HSP-70与细胞保护的研究进展.大连医科大学学报, 2007, 29(2): 194-196.
10. Malago JJ, Koninkx JF, van Dijk JE. The heat shock response and cytoprotection of the intestinal epithelium. Cell Stress Chaperones, 2002, 7(2):191-199.
11. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17(14):1709-1713.
12. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell, 2005, 97(3):185-196.
13. Ouko L, Ziegler TR, Gu LH, et al. Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem, 2004, 279(25): 26707-26715.
14. Matsuzawa S, Reed JC. Siah21, SIP and Ebi collaborate in a novel pathway forβ-catenin degradation linked to p53 response. Mol Cell, 2001, 7 (5) : 915 - 926.
15.金丹,陆付耳. PI3K在Ⅱ型糖尿病发病机制中的作用.医学综述, 2007, 13(1): 21-23.
16.王锋超,王涛,艾国平,等.不同伤情血清可有效激活IEC6细胞PI3K/Akt通路.第三军医大学学报, 2006, 28(6): 518-520.
17.张蒙,甘华田. PI3K/AKT信号传导通路与肠道炎症.华西医学, 2006, 21(1): 192-193.
18.薛景,刘芬菊. PI3K/Akt与胶质瘤辐射抗性.国外医学放射医学核医学分册, 2005, 29(1): 40-43.
19.姜勇,罗深秋主编.细胞信号转导的分子基础与功能调控.北京:科学出版社, 2005. 158-160.
20.冯秀艳,张志刚,赵仲华,等.饰胶蛋白聚糖对大鼠肾系膜细胞生长的抑制作用及其信号转导途径的研究.中华肾脏病学杂志, 2005, 21(9): 512-516.
21.杭春华,史继新,吴伟,等.创伤性脑损伤后脑组织c-fos表达及细胞凋亡.创伤外科杂志, 2007, (9)2: 146-149.
22. Lin J, Duna A. Raoof, Wang ZW, et al. Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma1. Neoplasia, 2006, 8(12): 1062-1071.
23.何伟珍,徐晓东.泛素-蛋白酶体途径与疾病.海南医学, 2000, 18(3): 141-142, 152.
24. Tashiro K, Pando MP, Kanegae Y, et al. Direct involvement of the ubiquitin-conjugating enzyme Ubc9/Hus5 in the degradation of IkappaBalpha. Proc Natl Acad Sci USA, 1997, 94(15):7862-7867.
25. Doelling JH, Phillips AR, Soyler-Ogretim G, et al. The ubiquitin-specific protease subfamily UBP3/UBP4 is essential for pollen development and transmission in Arabidopsis. Plant Physiol, 2007, 145(3):801-813.
26.顾岩.人胰岛素样生长因子-1与肠外营养.肠外与肠内营养, 2000, 7(2): 110-113.
27.牛亦农,邢念增,辛殿祺,等.聚集素抗LNCaP细胞凋亡作用的研究.中华泌尿外科杂志, 2006, 27(7): 486-489.
28. McLaughlin L, Zhu G, Mistry M, et al. Apolipoprotein/clusterin limits the severity of murine auto immune myocarditis. J Clin Invest, 2000, 106(9): 1105-1113.
29.付桂莉,许成蓉.聚集素与细胞凋亡关系的研究进展.临床口腔医学杂志, 2004, 20(9): 570-572.
30.陈涛,付小兵,伍津津,等. bFGF与MSCs自体移植对猪皮肤创面PCNA和Ⅷ-R Ag表达的影响.第三军医大学学报, 2007, 29(2): 91-93.
31.王剑,温树正.碱性成纤维细胞生长因子对周围神经损伤的修复作用的研究进展.内蒙古医学杂志, 2007, 39(2): 214-216.
32. Zhu YQ, Tan XD. TFF3 modulates NF-κB and a novel negative regulatory molecule ofNF-κB in intestinal epithelial cells via a mechanism distinct from TNF-α. Am J Physiol Cell Physiol, 2005, 289(5):C1085-1093.
33.王跃群,李永青,袁婺洲,等.人类T型钙通道α1G和α1H亚单位基因在细胞增殖中的功能比较.自然科学进展, 2005, 15 (11): 1305-1311.
34.刘伟,李庆军,卢绮萍. Caspase与细胞凋亡.新乡医学院学报, 2005, 22(1): 67-70.
35.周舟,张蕾,邓朝晖,等.辐射诱导IEC-6细胞GSK3β信号转导途径的激活与细胞凋亡的关系研究.辐射研究与辐射工艺学报, 2006, 24(3): 178-182.
36.赵忠伟,张云汉. TRAIL/APO-2L与神经胶质瘤细胞凋亡.河南大学学报(医学版), 2004, 23(4): 11-14.
37.王会平,龙贤辉,徐勤枝,等.基因芯片技术分析20cGyC射线照射人淋巴母细胞中差异表达的基因.辐射防护, 2006, 26(3): 152-156.
38. Hollier B, Harkin DG, Leavesley D, et al. Responses of keratinocytes to substrate-bound vitronectin: growth factor complexes. Exp Cell Res, 2005, 305(1): 221-232.
39. Hyde C, Hollier B, Anderson A, et al. Insulin-like growth factors (IGF) and IGF-binding proteins bound to vitronectin enhance keratinocyte protein synthesis and migration. J Invest Dermatol, 2004, 122(5): 1198-1206.
40.霍娟.哺乳动物细胞同源重组相关蛋白的研究进展.国外医学遗传学分册, 2001, 24(1): 24-27.
1. Kharbanda S, Saleem A, Shafman T, et al. Activation of the pp90rsk and mitogen-activated serine/threonine protein kinase by ionizing radiation. Proc Natl Acad Sci USA, 1994, 91(12): 5416-5420.
2. Sukhotnik I, Shteinberg D, Ben Lulu S, et al. Transforming growth factor-alpha stimulates enterocyte proliferation and accelerates intestinal recovery following methotrexate-induced intestinal mucositis in a rat and a cell culture model. Pediatr Surg Int, 2008, 24(12):1303-1311.
3. Edelblum KL, Washington MK, Koyama T, et al. Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB. Gastroenterology, 2008,135(2):539-551.
4. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
5. Tenney R, Stansfield K, Pekala PH. Interleukin 11 signaling in 3T3-L1 adipocytes. J Cell Physiol, 2005 , 202(1):160-166.
6. Duplomb L, Chaigne-Delalande B, Vusio P, et al. Soluble mannose 6-phosphate/insulin-like growth factor II (IGF-II) receptor inhibits interleukin-6-type cytokine-dependent proliferation by neutralization of IGF-II. Endocrinology, 2003, 144(12):5381-5389.
7. Luongo D, Mazzarella G, Della RF, et al. Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29. Mol Cell Biochem, 2002, 231(1-2):43-50.
8. Taupin D, Podolsky DK. Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology, 1999, 116(5):1072-1080.
9. Dieckgraefe BK, Weems DM. Epithelial injury induces egr-1 and fos expression by a pathway involving protein kinase C and ERK. Am J Physiol, 1999, 276(21):322-330.
10.郑曙云,付小兵,徐建国. MAPK信号传导通路与肠损伤后黏膜上皮修复.中国危重病急救医学, 2004, 16(1): 59-62.
11. van der Wijk T, Dorrestijn J, Narumiya S, et al. Osmotic swelling-induced activation of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2 in intestine 407 cells involves the Ras/Raf-signalling pathway. Biochem J, 1998, 331 (3):863-869.
12. Kim CS, Kim JK, Nam SY, et al. Low-dose radiation stimulates the proliferation of normal human lung fibroblasts via a transient activation of Raf and Akt. Mol Cells, 2007, 24(3):424-430.
13. Casarez EV, Dunlap-Brown ME, Conaway MR, et al. Radiosensitization and modulation of p44/42 mitogen-activated protein kinase by 2-Methoxyestradiol in prostate cancer models. Cancer Res, 2007, 67(17):8316-8324.
14. Kumar P, Coltas IK, Kumar B, et al. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
15. Yacoub A, Park JS, Qiao L, et al. MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 2001, 77(10):1067-1078.
16. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
17.左红艳.不同频段电磁辐射致大鼠海马损伤效应及蛋白质组学研究.军事医学科学院博士学位论文, 2007.
18.周舟,王小华, Igisu Hideki,等.辐射诱导IEC-6细胞MAPK信号转导途径的激活.辐射研究与辐射工艺学报, 2002, 20(2): 137-145.
19. Lee S, Fang L, Igarashi M, et al. Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53. Proc Natl Acad Sci USA, 2000, 97, 8302?8305.
20. Golding SE, Rosenberg E, Neill S, et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res, 2007, 67(3):1046-53.
21. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int J Oncol, 2006, 29(1):163-168.
22. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
23. Naugler KM, Baer KA, Ropeleski MJ. Interleukin-11 antagonizes Fas ligand-mediated apoptosis in IEC-18 intestinal epithelial crypt cells: role of MEK and Akt-dependent signaling. Am J Physiol Gastrointest Liver Physiol, 2008, 294(3): 728-737.
24. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
25. Golding SE, Rosenberg E, Neill S, et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res, 2007, 67(3):104610-104653.
26. MacLaine NJ, Wood MD, Holder JC, et al. Sensitivity of normal, paramalignant, and malignant human urothelial cells to inhibitors of the epidermal growth factor receptor signaling pathway. Mol Cancer Res, 2008, 6(1):53-63.
27. Hamed H, Hawkins W, Mitchell C, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo. Mol Cancer Ther, 2008, 7(3):616-629.
28. Liao YH, Hsu SM, Huang PH. ARMS depletion facilitates UV irradiation induced apoptotic cell death in melanoma. Cancer Res, 2007, 67(24):11547-11556.
29. Kim BY, Kim KA, Kwon O, et al. NF-kappa B inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation. Carcinogenesis, 2005, 26(8):1395-1403.
30. Hagan MP, Yacoub A, Dent P. Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. J Cell Biochem, 2007, 101(6):1384-1393.
31. Yacoub A, Miller A, Caron RW,et al. Radiotherapy-induced signal transduction. Endocr Relat Cancer, 2006, 13 Suppl 1:S99-114.
32. Sheng H, Shao J, Townsend CM J, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
1.薛景,刘芬菊. PI3K/Akt与胶质瘤辐射抗性.国外医学.放射医学核医学分册, 2005, 29(1): 40-43.
2. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kB transcription factors. Oncogene, 1999, 18(49): 6910-6924.
3. Roche S, Downward J, Raynal P, et al. A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction, Mol Cell Biol, 1998, 18:7119–7129.
4. Sheng H, Shao J, Townsend CM J, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
5. Huet C, Sahuquillo-Merino C, Coudrier E, et al. Absorptive and mucussecreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation. J Cell Biol, 1987, 105:345-357.
6. Shao J, Evers BM, Sheng H. Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res, 2004, 64(1):229-235.
7. Tamura T, Cui X, Sakaguchi N, et al. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol, 2008, 46(9):3080-3089.
8. Greenspon J, Li R, Xiao L, et al. Sphingosine-1-phosphate protects intestinal epithelial cells from apoptosis through the Akt signaling pathway. Dig Dis Sci, 2009, 54(3):499-510.
9. Uemura T, Nakayama T, Kusaba T, et al.The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
10.田梅,朴春姬,李修义,等. IR诱导pEgr-hPTEN表达增强其体外抗肿瘤作用.吉林大学学报(医学版), 2005, 31(3): 330-333.
11. Montgomery RK, Breault DT. Small intestinal stem cell markers. J Anat, 2008, 213(1):52-8.
12. Wang Q, Zhou Y, Wang X, et al. Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. Cancer Res, 2007, 67(16):7773-7781.
13. G·克劳斯著,孙超,刘景生,王子镐,等译.信号转导与调控的生物化学.北京,化学工业出版社,第三版, 2005.187-395.
14. Wang ML, Keilbaugh SA, Cash-Mason T, et al. Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways. Am J Physiol Gastrointest Liver Physiol, 2008, 295(5): 1122-1130.
15. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
16. Uemura T, Nakayama T, Kusaba T, et al. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
17. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
18. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
19. Fuhrer DK, Yang YC. Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11. Exp Hematol, 1996, 24(2):195-203.
20. Nakayama T, Yoshizaki A, Izumida S, et al. Expression of interleukin-11 (IL-11) and IL-11 receptor alpha in human gastric carcinoma and IL-11 upregulates the invasive activity of human gastric carcinoma cells. Int J Oncol, 2007, 30(4):825-833.
21. Oka N, Tanimoto S, Taue R, et al. Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci, 2006, 97(10):1093-1098.
22. Krystal GW, Sulanke G, Litz J. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. Mol Cancer Ther, 2002, 1(11):913-922.
23. Hagan MP, Yacoub A, Dent P. Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. J Cell Biochem, 2007, 101(6):1384-1393.
24. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
1. Shelton JG, Steelman LS, White ER, et al. Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle, 2004, 3(3):372-379.
2. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2):189-218.
3.袁向飞,陆敏. Ras/MAPK与PI3K/Akt信号转导通路及其相互作用.国际检验医学杂志, 2006, 27(3): 261-263.
4. G·克劳斯著,孙超,刘景生,王子镐,等译.信号转导与调控的生物化学.化学工业出版社,第三版, 2005.187-189.
5. Menges CW, McCance DJ. Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor. Oncogene, 2008, 27(20):2934-2940.
6. Marino M, Acconcia F, Trentalance A. Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell, 2003, 14(6):2583-2591.
7. López-Pedrera C, Barbarroja N, Buendía P, et al. Promyelocytic leukemia retinoid signaling targets regulate apoptosis, tissue factor and thrombomodulin expression. Haematologica, 2004, 89(3):286-295.
8. Yamboliev IA, Wiesmann KM, Singer CA, et al. Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle. Am J Physiol Cell Physiol, 2000, 279(2): 352-360.
9. Schmidt EK, Fichelson S, Feller SM. PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors. BMC Biol, 2004,2:7.
10. Wang CC, Cirit M, Haugh JM. PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk. Mol Syst Biol, 2009, 5:246.
11. Lee MY, Jo SD, Lee JH, et al. L-leucine increases [3H]-thymidine incorporation in chicken hepatocytes: involvement of the PKC, PI3K/Akt, ERK1/2, and mTOR signaling pathways. J Cell Biochem, 2008, 105(6):1410-1419.
12. Campbell M, Allen WE, Sawyer C, et al. Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res, 2004, 95(4):380-388.
13. Levinthal DJ, DeFranco DB. Transient phosphatidylinositol 3-kinase inhibition protects immature primary cortical neurons from oxidative toxicity via suppression of extracellular signal-regulated kinase activation. J Biol Chem, 2004, 279(12):11206-11213.
14. Campbell M, Allen WE, Sawyer C, et al. Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res, 2004, 95(4):380-388.
15. Kim YM, Namkoong S, Yun YG, et al. Water extract of Korean red ginseng stimulatesangiogenesis by activating the PI3K/Akt-dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells. Biol Pharm Bull, 2007, 30(9):1674-1679.
16. Bradley EW, Ruan MM, Vrable A, et al. Pathway crosstalk between Ras/Raf and PI3K in promotion of M-CSF-induced MEK/ERK-mediated osteoclast survival. J Cell Biochem, 2008, 104(4):1439-1451.
17. Lee JT Jr, Steelman LS, Chappell WH, et al. Akt inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells. Cell Cycle, 2008, 7(5):631-636.
18. Gervais M, Dugourd C, Muller L, et al. Akt down-regulates ERK1/2 nuclear localization and angiotensin II-induced cell proliferation through PEA-15. Mol Biol Cell, 2006, 17(9):3940-3951.
19. Hatakeyama M, Kimura S, Naka T, et al. A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. Biochem J, 2003, 373(Pt 2):451-463.
20. Dai R, Chen R, Li H. Cross-talk between PI3K/Akt and MEK/ERK pathways mediates endoplasmic reticulum stress-induced cell cycle progression and cell death in human hepatocellular carcinoma cells. Int J Oncol, 2009, 34(6):1749-1757.
21. Bouali S, Chrétien AS, Ramacci C, et al. PTEN expression controls cellular response to cetuximab by mediating PI3K/AKT and RAS/RAF/MAPK downstream signaling in KRAS wild-type, hormone refractory prostate cancer cells. Oncol Rep, 2009, 21(3):731-735.
22. He S, Dibas A, Yorio T, et al. Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells. Exp Biol Med (Maywood), 2007, 232(3):370-384.
23. Romano D, Pertuit M, Rasolonjanahary R, et al. Regulation of the RAP1/RAF-1/extracellularly regulated kinase-1/2 cascade and prolactin release by the phosphoinositide 3-kinase/AKT pathway in pituitary cells. Endocrinology, 2006, 147(12):6036-6045.
24. Liu L, Xie Y, Lou L. PI3K is required for insulin-stimulated but not EGF-stimulated ERK1/2 activation. Eur J Cell Biol, 2006, 85(5):367-374.
1. Brown M. What causes the radiation gastrointestinal syndrome: overview. Int J Radiat Oncol Biol Phys, 2008, 70(3): 799-800.
2. Potten CS, Wilson JW, Booth C. Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells, 1997, 15(2):82-93.
3. Harnois C, Demers MJ, Bouchard V, et al. Human intestinal epithelial crypt cell survival and death: Complex modulations of Bcl-2 homologs by Fak, PI3-K/Akt-1, MEK/Erk, and p38 signaling pathways. J Cell Physiol, 2004, 198(2):209-222.
4. Kumar P, Coltas IK, Kumar B, et al. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
5.弓清梅,李建强,刘卓拉.大鼠急性肺损伤过程中STAT3的活化对bcl-2/ bax表达及细胞凋亡的影响.中国药物与临床, 2007, (7)1: 35-37.
6. Tamura T, Cui X, Sakaguchi N, et al. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol, 2008, 46(9):3080-3089.
7. Matsuu-Matsuyama M, Shichijo K, Okaichi K, et al. Sucralfate protects intestinal epithelial cells from radiation-induced apoptosis in rats. J Radiat Res (Tokyo), 2006, 47(1):1-8.
8. Park E, Lee NH, Joo HG, et al. Modulation of apoptosis of eckol against ionizing radiation in mice. Biochem Biophys Res Commun, 2008, 372(4):792-797.
9. Matsuu-Matsuyama M, Shichijo K, Okaichi K, et al. Protection by polaprezinc against radiation-induced apoptosis in rat jejunal crypt cells. J Radiat Res (Tokyo), 2008, 49(4):341-347.
10. Watson AJ, Pritchard DM. Lessons from genetically engineered animal models. VII. Apoptosis in intestinal epithelium: lessons from transgenic and knockout mice. Am J Physiol Gastrointest Liver Physiol, 2000, 278(1):G1-5.
11. Shaposhnikov Y, Maheshwari Y, Sykes DE, et al. Intestinal cell apoptosis and Bcl-2 expression. Cell Death Differ, 1996, 3(1):125-130.
12. Pritchard DM, Potten CS, Korsmeyer SJ, et al. Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene, 1999, 18(51):7287-7293.
13. Coopersmith CM, O'Donnell D, Gordon JI. Bcl-2 inhibits ischemia-reperfusion-induced apoptosis in the intestinal epithelium of transgenic mice. Am J Physiol, 1999, 276(3 Pt 1):G677-686.
14. Duckworth CA, Pritchard DM. Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice. Gastroenterology, 2009, 136(3):943-952.
15. Hendry JH, Broadbent DA, Roberts SA, et al. Effects of deficiency in p53 or bcl-2 on the sensitivity of clonogenic cells in the small intestine to low dose-rate irradiation. Int J Radiat Biol. 2000, 76(4):559-565.
16. Van Houten N, Blake SF, Li EJ, et al. Elevated expression of Bcl-2 and Bcl-x by intestinal intraepithelial lymphocytes: resistance to apoptosis by glucocorticoids and irradiation. Int Immunol, 1997, 9(7):945-953.
17. Tessner TG, Muhale F, Riehl TE, et al. Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation. J Clin Invest, 2004, 114(11):1676-1685.
18. G·克劳斯著,孙超,刘景生,等译.信号转导与调控的生物化学.第三版, 2005, 394-395.
19. Gui C, Wang JA, He AN, et al. Heregulin protects mesenchymal stem cells from serum deprivation and hypoxia-induced apoptosis. Mol Cell Biochem, 2007, 305(1-2):171-178.
20. Li CR, Zhou Z, Zhu D, et al. Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. Int J Biochem Cell Biol, 2007, 39(2):426-438.
21. Li LH, Wu LJ, Tashiro SI, et al. The roles of Akt and MAPK family members in silymarin's protection against UV-induced A375-S2 cell apoptosis. Int Immunopharmacol, 2006, 6(2):190-197.
1.毛秉智,陈家佩,主编.急性放射病基础与临床.北京:军事医学科学出版社,第一版, 2002.
2. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17(14):1709-1713.
3. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell, 2005, 97(3): 185-196.
4. Ouko L, Ziegler TR, Gu LH, et al. Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem, 2004, 279(25): 26707-26715.
5. Pinto D, Clevers H. Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res, 2005, 306(2):357-363.
6.梅文燕,丁小燕. Wnt信号途径及其作用机制.生命的化学, 2000, 20(5): 193-197.
7. Ogasawara N, Tsukamoto T, Mizoshita T, Inada K, Cao X, Takenaka Y, Joh T, Tatematsu M. Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human gastric cancer. Histopathology,2006, 49(6):612-621.
8.姜祖韵,袁毅君,明镇寰,等.维持胚胎干细胞自我更新分子机制的研究进展.生物化学与生物物理进展, 2004, 31(11): 965-968.
9.王启明,杨开明,周鸿鹰,等.β-catenin在大鼠胚胎肝脏发育和肝癌发生中的作用.四川大学学报(医学版), 2006, 37(6):872-875.
10.林琼琼,李锦添,王敏. Wnt通路中APC、β-catenin及c-myc与大肠癌的关系.广西医学, 2006, 28(2): 233-235.
11. Fujimura N, Vacik T, Machon O, et al. Wnt-mediated down-regulation of Sp1 target genes by a transcriptional repressor Sp5. J Biol Chem, 2007, 282(2):1225-1237.
12.殷河慧,廖文俊. Wnt信号转导通路及其在皮肤肿瘤中的作用.国外医学皮肤性病学分册, 2005, 31(2):119-121.
13.黄勇,窦科峰.β-连环蛋白在原发性肝细胞癌中的表达及其临床意义.第四军医大学学报, 2002, 23(12): 1103-1105.
14. Batlle E, Henderson JT, Beghtel H, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell, 2002, 111(2):251-263.
15. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17(14):1709-1713.
16. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell, 2005, 97(3):185-196.
17. Ouko L, Ziegler TR, Gu LH, et al. Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem, 2004, 279(25):26707-26715.
18. Wong MH, Huelsken J, Birchmeier W, et al. Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkuhn is perturbed by stimulation of Lef-1/beta-catenin signaling. J Biol Chem, 2002, 277(18):15843-15850.
19. Mariadason JM, Bordonaro M, Aslam F, et al. Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res, 2001, 61(8):3465-3471.
20. Horn K, Batlle E, Coudreuse D, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell, 2002, 111(2):241-250.
21. Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol, 2007 Feb 15; [Epub ahead of print]
22. Wong MH, Rubinfeld B, Gordon JI. Effects of forced expression of an NH2-terminal truncated beta-Catenin on mouse intestinal epithelial homeostasis. J Cell Biol, 1998, 141(3):765-777.
23. Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet, 1998, 19(4):379-383.
24. Muncan V, Sansom OJ, Tertoolen L, et al. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol Cell Biol, 2006, 26(22):8418-8426.
25. Hao X, Tomlinson I, Ilyas M, et al. Reciprocity between membranous and nuclear expression of beta-catenin in colorectal tumours. Virchows Arch, 1997, 431(3):167-172.
26. Murata M, Iwao K, Miyoshi Y, et al. Molecular and biological analysis of carcinoma of thesmall intestine: beta-catenin gene mutation by interstitial deletion involving exon 3 and replication error phenotype. Am J Gastroenterol, 2000, 95(6):1576-1580.
27. Iwamoto M, Ahnen DJ, Franklin WA, et al. Expression of beta-catenin and full-length APC protein in normal and neoplastic colonic tissues. Carcinogenesis, 2000, 21(11):1935-1940.
28. Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science, 1997, 275(5307):1784-1787.
29. Van der Flier LG, Sabates-Bellver J, Oving I, et al. The Intestinal Wnt/TCF Signature. Gastroenterology, 2007, 132(2):628-632.
30. Mariadason JM, Bordonaro M, Aslam F, et al.Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res, 2001, 61(8):3465-3471.
31. Mei JM, Hord NG, Winterstein DF, et al. Differential formation of beta-catenin/lymphoid enhancer factor-1 DNA binding complex induced by nitric oxide in mouse colonic epithelial cells differing in adenomatous polyposis coli (Apc) genotype. Cancer Res, 2000, 60(13):3379-3383.
32. Mezhybovska M, Wikstrom K, Ohd JF, et al. The inflammatory mediator leukotriene D4 induces beta-catenin signaling and its association with antiapoptotic Bcl-2 in intestinal epithelial cells. J Biol Chem, 2006, 281(10):6776-6684.
33. Kucharczak J, Simmons MJ, Fan Y, et al.To be, or not to be: NF-κB is the answer-role of Rel/NF-κB in the regulation of apoptosis. Oncogene, 2003, 22(56):8961-8982.
34. Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death-a new approach to cancer therapy. J Clin Invest, 2005, 115(10): 2625-2632.
35. Karrasch T, Jobin C. NF-kappaB and the intestine: friend or foe? Inflamm Bowel Dis, 2008, 14(1):114-124.
36. Chen F, Castranova V, Shi X. New Insights into the Role of Nuclear Factor-κB in Cell Growth Regulation. Am J Pathol, 2001, 159(2):387-397.
37. Dajani R, Sanlioglu S, Zhang Y, et al. Pleiotropic functions of TNF-alpha determine distinct IKKbeta-dependent hepatocellular fates in response to LPS. Am J Physiol Gastrointest Liver Physiol, 2007, 292(1):G242-252.
38. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
39. Wang Y, Meng A, Lang H, et al. Activation of nuclear factor kappaB in vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res, 2004, 64(17):6240-6246.
40. Egan LJ, Eckmann L, Greten FR, et al. IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proc Natl Acad Sci USA, 2004, 101(8):2452-2457.
41. Peng Z, Peng L, Fan Y, et al. A critical role for IkappaB kinase beta in metallothionein-1 expression and protection against arsenic toxicity. J Biol Chem, 2007, 282(29):21487-21496.
42. Zaph C, Troy AE, Taylor BC, et al. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature, 2007, 446(7135):552-556
43.薛景,刘芬菊. PI3K/Akt与胶质瘤辐射抗性.国外医学.放射医学核医学分册, 2005, 29(1): 40-43.
44. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kB transcription factors. Oncogene, 1999, 18(49): 6910-6924.
45. Roche S, Downward J, Raynal P, et al. A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction, Mol Cell Biol, 1998, 18:7119–7129.
46. Sheng H, Shao J, Townsend CM Jr, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
47. Huet C, Sahuquillo-Merino C, Coudrier E, et al. Absorptive and mucussecreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation. J Cell Biol, 1987, 105:345-357.
48. Shao J, Evers BM, Sheng H. Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res, 2004, 64(1):229-235.
49. Tamura T, Cui X, Sakaguchi N,et al. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol, 2008, 46(9):3080-3089.
50. Greenspon J, Li R, Xiao L, et al. Sphingosine-1-phosphate protects intestinal epithelial cells from apoptosis through the Akt signaling pathway. Dig Dis Sci, 2009, 54(3):499-510.
51. Uemura T, Nakayama T, Kusaba T, et al. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
52. G·克劳斯著,孙超,刘景生,王子镐,等译.信号转导与调控的生物化学.北京,化学工业出版社,第三版, 2005.187-395.
53. Wang ML, Keilbaugh SA, Cash-Mason T, et al. Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways. Am J Physiol Gastrointest Liver Physiol, 2008, 295(5): 1122-1130.
54. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
55. Uemura T, Nakayama T, Kusaba T, et al. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
56. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-76.
57. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
58. Fuhrer DK, Yang YC. Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11. Exp Hematol, 1996, 24(2):195-203.
59. Kharbanda S, Saleem A, Shafman T, et al. Activation of the pp90rsk and mitogen-activated serine/threonine protein kinase by ionizing radiation. Proc Natl Acad Sci USA, 1994, 91(12): 5416-5420.
60. Sukhotnik I, Shteinberg D, Ben Lulu S, et al. Transforming growth factor-alpha stimulates enterocyte proliferation and accelerates intestinal recovery following methotrexate-induced intestinal mucositis in a rat and a cell culture model. Pediatr Surg Int, 2008, 24(12):1303-1311.
61. Edelblum KL, Washington MK, Koyama T, et al. Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB. Gastroenterology, 2008, 135(2):539-551.
62. Luongo D, Mazzarella G, Della RF, et al. Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29. Mol Cell Biochem, 2002, 231(1-2):43-50.
63. Taupin D, Podolsky DK. Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology, 1999, 116(5):1072-1080.
64. Dieckgraefe BK, Weems DM. Epithelial injury induces egr-1 and fos expression by a pathway involving protein kinase C and ERK. Am J Physiol, 1999, 276(21):322-330.
65.郑曙云,付小兵,徐建国. MAPK信号传导通路与肠损伤后黏膜上皮修复.中国危重病急救医学, 2004, 16(1): 59-62.
66. Kumar P, Coltas IK, Kumar B, et alJ. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
67. van der Wijk T, Dorrestijn J, Narumiya S, et al. Osmotic swelling-induced activation of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2 in intestine 407 cells involves the Ras/Raf-signalling pathway. Biochem J, 1998, 331 (3):863-869.
68. Yacoub A, Park JS, Qiao L, et al. MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 2001, 77(10):1067-1078.
69. Grana TM, Rusyn EV, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
70.左红艳.不同频段电磁辐射致大鼠海马损伤效应及蛋白质组学研究.军事医学科学院博士学位论文, 2007.
71.周舟,王小华, Igisu Hideki,等.辐射诱导IEC-6细胞MAPK信号转导途径的激活.辐射研究与辐射工艺学报, 2002, 20(2): 137-145.
72. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int J Oncol, 2006, 29(1):163-168.
73. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
74. Naugler KM, Baer KA, Ropeleski MJ. Interleukin-11 antagonizes Fas ligand-mediated apoptosis in IEC-18 intestinal epithelial crypt cells: role of MEK and Akt-dependent signaling. Am J Physiol Gastrointest Liver Physiol, 2008, 294(3): 728-737.
75. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive andproliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
76.宋伦,沈倍奋. Jak/STAT信号转导途径研究新进展.免疫学杂志, 2000, 16(1): 68-71.
77. Heinrich PC, Behrmann I, Muller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J, 1998, 334 ( Pt 2): 297-314.
78. Gao H, Guo RF, Speyer CL, et al. Stat3 activation in acute lung injury. J Immunol, 2004, 172(12):7703-7712.
79. Tebbutt NC, Giraud AS, Inglese M, et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med, 2002, 8(10):1089-1097.
80. Musso A, Dentelli P, Carlino A, et al. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis, 2005, 11(2):91-98.
81. Mudter J, Weigmann B, Bartsch B, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol, 2005, 100(1):64-72.
82. Alonzi T, Newton IP, Bryce PJ, et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine, 2004, 26(2):45-56.
83. Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci USA, 2003, 100(4):1879-1884.
84. Zushi S, Shinomura Y, Kiyohara T, et al. STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer, 1998, 78(3):326-330.
85. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem. 2004, 279(11):10304-10315.
86. Ropeleski MJ, Tang J, Walsh-Reitz MM, et al. Interleukin-11-induced heat shock protein 25 confers intestinal epithelial-specific cytoprotection from oxidant stress. Gastroenterology, 2003, 124(5):1358-1368.
87. Shelton JG, Steelman LS, White ER, et al. Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle, 2004, 3(3):372-379.
88. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2):189-218.
89. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2): 189-218.
2.马林,周桂霞,冯林春主编.恶性肿瘤高LET(重离子、快中子)放射治疗学.军事医学科学出版社,第一版, 2007. 133-135.
3.毛志达.快中子治疗肿瘤的临床进展.癌症, 1998, 17(1): 71-74.
4. Yeoh AS, Gibson RJ, Yeoh EE, et al. A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappa B, COX-1 and COX-2. Mol Cancer Ther, 2007, 6(8):2319-2327.
5. Coopersmith CM, Gordon JI. gamma-ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53. Oncogene, 1997, 15(2):131-141.
6.毛秉智,陈家佩主编.急性放射病基础与临床.军事医学科学出版社,第一版, 2002, 101-131.
7.王宝勤,王珏,谭洪玲,等.细胞因子对中子和γ射线照射小鼠的辐射防护作用及作用机理研究.中华放射医学与防护杂志, 1997, 17(6): 404-407.
8. Butturini A, De Souza PC, Gale RP. Use of recombinant granulocyte-macrophage colony stimulating factor in the Brazil radiation accident. Lancet, 1988, 2(8609):1447-1475.
9. Brandao CE, Oliveira AR, Valverde NJ , et al. Clinical and hematological aspects of 137Cs: the Go iania radiation accident. Health Phys, 1991, 60(1): 31-39.
10.郝静,罗庆良,熊国林,等. rhIL-11不同时间给药对急性放射病猕猴造血系统的影响.中华放射医学与防护杂志, 2001, 21(1):31-34.
11.高亚杰,孙红,乔京京,等.重组人白细胞介素-11对化疗后血小板减少症的治疗作用.中国新药与临床杂志, 2003, 22(5):266-268.
12.王瑞娟,彭瑞云.白介素-11在放射性肠道损伤中的作用研究.中华放射医学与防护杂志, 2005, 25(5): 494-496.
13. Kuenzler KA, Pearson PY, Schwartz MZ. IL-11 pretreatment reduces cell death after intestinal ischemia-reperfusion. J Surg Res, 2002, 108(2):268-272.
14. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11): 10304-10315.
15. Alavi K, Prasad R, Lundgren K, et al. Interleukin-11 enhances small intestine absorptive function and mucosal mass after intestinal adaptation. J Pediatr Surg, 2000, 35(2):371-374.
16. Potten CS. Interleukin-11 protects the clonogenic stem cells in murine small-intestine crypts from impairment of their reproductive capacity by radiation. Int J Cancer, 1995, 62(3): 356-361.
17. Barton VA, Hall MA, Hudson KR, et al. Interleukin-11 signals through the formation of a hexameric receptor complex. J Biol Chem, 2000, 275(46):36197-36203.
18. Du X, Williams DA. Interleukin-11: review of molecular, cell biology and clinical use. Blood, 1997, 89(11):3897-3908.
19. Tenney R, Stansfield K, Pekala PH. Interleukin 11 signaling in 3T3-L1 adipocytes. J Cell Physiol, 2005, 202(1):160-166.
20. Rajgopal R, Butcher M, Weitz JI, et al. Heparin synergistically enhances interleukin-11 signaling through up-regulation of the MAPK pathway. J Biol Chem, 2006, 281(30): 20780-20787.
21. Wang XY, Fuhrer DK, Marshall MS, et al. Interleukin-11 Induces Complex Formation of Grb2, Fyn, and JAK2 in 3T3L1 Cells. J Biol Chem, 1995, 270(47): 27999-28002.
22.朱婉儿,胡长春,谢文婷,等.慢性应激对大鼠海马Akt/FKHR1信号通路活性的影响.心理学报, 2007, 39(4):656-661.
23.张蒙,甘华田. PI3K/AKT信号传导通路与肠道炎症.华西医学, 2006, 21(1): 192-193.
24. Tebbutt NC, Giraud AS, Inglese M,et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med, 2002, 8(10):1089-1097.
25. Naka T, Kishimoto T. Joint disease caused by defective gp130-mediated STAT signaling. Arthritis Res, 2002, 4(3):154-156.
26. Ernst M, Inglese M, Waring P, et al. Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med, 2001, 194(2):189-203.
27. Musso A, Dentelli P, Carlino A, et al. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis, 2005, 11(2):91-98.
28. Mudter J, Weigmann B, Bartsch B, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol, 2005, 100(1):64-72.
29. Alonzi T, Newton IP, Bryce PJ, et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine, 2004, 26(2):45-56.
30. Mogila V, Xia F, Li WX. An intrinsic cell cycle checkpoint pathway mediated by MEK and ERK in Drosophila. Dev Cell, 2006, 11(4):575-582.
31. Kumar P, Coltas IK, Kumar B, et al. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
32. Yacoub A, Park JS, Qiao L, et al. MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 2001, 77(10):1067-1078.
33. Golding SE, Rosenberg E, Neill S, et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res, 2007, 67(3):1046-1053.
34. Kim CS, Kim JK, Nam SY, et al. Low-dose radiation stimulates the proliferation of normal human lung fibroblasts via a transient activation of Raf and Akt. Mol Cells, 2007, 24(3):424-430.
35. Sheng H, Shao J, Townsend CM, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
36. Marino M, Acconcia F, Trentalance A. Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell, 2003, 14(6):2583-2591.
37. Bradley EW, Ruan MM, Vrable A, et al. Pathway crosstalk between Ras/Raf and PI3K in promotion of M-CSF-induced MEK/ERK-mediated osteoclast survival. J Cell Biochem, 2008, 104(4):1439-1451.
38. Shelton JG, Steelman LS, White ER, et al. Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle, 2004, 3(3):372-379.
39. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2):189-218.
40. Wang RJ, Peng RY, Fu KF, et al. Effect of recombinant human interleukin-11 on expressions of interleukin-11 receptorα-chain and glycoprotein 130 in intestinal epithelium cell line-6 after neutron irradiation. World J Gastroenterol, 2006, 12(19): 3055-3059.
41.王瑞娟,彭瑞云,高亚兵,等. IL-11保护中子照射后肠上皮损伤的Jak/STAT信号转导机制研究.细胞与分子免疫学杂志, 2009, 25(1): 27-30.
42.王瑞娟,彭瑞云,韩瑞刚,等. IL-11对中子辐射肠道损伤保护作用的定量病理研究.中国体视学与图像分析, 2006, 11(2): 139-143.
1.毛秉智,陈家佩,主编.急性放射病基础与临床.军事医学科学出版社,第一版, 2002. 102-105.
2.蔡文琴,王伯云编著.实用免疫细胞化学与核酸分子杂交技术.四川科学技术出版社,第一版, 1994: 72-89.
3.毛秉智,陈家佩,主编.急性放射病基础与临床.军事医学科学出版社, 2002. 163-197.
4.罗庆良,从玉文,郝静,等.造血因子与急性放射病.解放军医学杂志, 2005, 30(3): 186-190.
5.吕秋军,高月.白介素11抗辐射损伤作用的研究进展.中华放射医学与防护杂志, 2000, 20(5): 369-370.
6. Frasca D, Guidi F, Arbitrio M, et al. Use of hematopoietic cytokines to accelerate the recovery of the immune system in irradiated mice. Exp Hematol, 1997, 25(11):1167-1171.
7. Shroff EH, Snyder C, Chandel NS. Role of Bcl-2 family members in anoxia induced cell death. Cell Cycle, 2007, 6(7): 807-809.
8.刘玲玉,孟玉强,杨学冬.热休克蛋白生物学作用的研究进展.阴山学刊, 2007, 21(1): 61-64.
9.马旭,吕刚. HSP-70与细胞保护的研究进展.大连医科大学学报, 2007, 29(2): 194-196.
10. Malago JJ, Koninkx JF, van Dijk JE. The heat shock response and cytoprotection of the intestinal epithelium. Cell Stress Chaperones, 2002, 7(2):191-199.
11. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17(14):1709-1713.
12. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell, 2005, 97(3):185-196.
13. Ouko L, Ziegler TR, Gu LH, et al. Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem, 2004, 279(25): 26707-26715.
14. Matsuzawa S, Reed JC. Siah21, SIP and Ebi collaborate in a novel pathway forβ-catenin degradation linked to p53 response. Mol Cell, 2001, 7 (5) : 915 - 926.
15.金丹,陆付耳. PI3K在Ⅱ型糖尿病发病机制中的作用.医学综述, 2007, 13(1): 21-23.
16.王锋超,王涛,艾国平,等.不同伤情血清可有效激活IEC6细胞PI3K/Akt通路.第三军医大学学报, 2006, 28(6): 518-520.
17.张蒙,甘华田. PI3K/AKT信号传导通路与肠道炎症.华西医学, 2006, 21(1): 192-193.
18.薛景,刘芬菊. PI3K/Akt与胶质瘤辐射抗性.国外医学放射医学核医学分册, 2005, 29(1): 40-43.
19.姜勇,罗深秋主编.细胞信号转导的分子基础与功能调控.北京:科学出版社, 2005. 158-160.
20.冯秀艳,张志刚,赵仲华,等.饰胶蛋白聚糖对大鼠肾系膜细胞生长的抑制作用及其信号转导途径的研究.中华肾脏病学杂志, 2005, 21(9): 512-516.
21.杭春华,史继新,吴伟,等.创伤性脑损伤后脑组织c-fos表达及细胞凋亡.创伤外科杂志, 2007, (9)2: 146-149.
22. Lin J, Duna A. Raoof, Wang ZW, et al. Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma1. Neoplasia, 2006, 8(12): 1062-1071.
23.何伟珍,徐晓东.泛素-蛋白酶体途径与疾病.海南医学, 2000, 18(3): 141-142, 152.
24. Tashiro K, Pando MP, Kanegae Y, et al. Direct involvement of the ubiquitin-conjugating enzyme Ubc9/Hus5 in the degradation of IkappaBalpha. Proc Natl Acad Sci USA, 1997, 94(15):7862-7867.
25. Doelling JH, Phillips AR, Soyler-Ogretim G, et al. The ubiquitin-specific protease subfamily UBP3/UBP4 is essential for pollen development and transmission in Arabidopsis. Plant Physiol, 2007, 145(3):801-813.
26.顾岩.人胰岛素样生长因子-1与肠外营养.肠外与肠内营养, 2000, 7(2): 110-113.
27.牛亦农,邢念增,辛殿祺,等.聚集素抗LNCaP细胞凋亡作用的研究.中华泌尿外科杂志, 2006, 27(7): 486-489.
28. McLaughlin L, Zhu G, Mistry M, et al. Apolipoprotein/clusterin limits the severity of murine auto immune myocarditis. J Clin Invest, 2000, 106(9): 1105-1113.
29.付桂莉,许成蓉.聚集素与细胞凋亡关系的研究进展.临床口腔医学杂志, 2004, 20(9): 570-572.
30.陈涛,付小兵,伍津津,等. bFGF与MSCs自体移植对猪皮肤创面PCNA和Ⅷ-R Ag表达的影响.第三军医大学学报, 2007, 29(2): 91-93.
31.王剑,温树正.碱性成纤维细胞生长因子对周围神经损伤的修复作用的研究进展.内蒙古医学杂志, 2007, 39(2): 214-216.
32. Zhu YQ, Tan XD. TFF3 modulates NF-κB and a novel negative regulatory molecule ofNF-κB in intestinal epithelial cells via a mechanism distinct from TNF-α. Am J Physiol Cell Physiol, 2005, 289(5):C1085-1093.
33.王跃群,李永青,袁婺洲,等.人类T型钙通道α1G和α1H亚单位基因在细胞增殖中的功能比较.自然科学进展, 2005, 15 (11): 1305-1311.
34.刘伟,李庆军,卢绮萍. Caspase与细胞凋亡.新乡医学院学报, 2005, 22(1): 67-70.
35.周舟,张蕾,邓朝晖,等.辐射诱导IEC-6细胞GSK3β信号转导途径的激活与细胞凋亡的关系研究.辐射研究与辐射工艺学报, 2006, 24(3): 178-182.
36.赵忠伟,张云汉. TRAIL/APO-2L与神经胶质瘤细胞凋亡.河南大学学报(医学版), 2004, 23(4): 11-14.
37.王会平,龙贤辉,徐勤枝,等.基因芯片技术分析20cGyC射线照射人淋巴母细胞中差异表达的基因.辐射防护, 2006, 26(3): 152-156.
38. Hollier B, Harkin DG, Leavesley D, et al. Responses of keratinocytes to substrate-bound vitronectin: growth factor complexes. Exp Cell Res, 2005, 305(1): 221-232.
39. Hyde C, Hollier B, Anderson A, et al. Insulin-like growth factors (IGF) and IGF-binding proteins bound to vitronectin enhance keratinocyte protein synthesis and migration. J Invest Dermatol, 2004, 122(5): 1198-1206.
40.霍娟.哺乳动物细胞同源重组相关蛋白的研究进展.国外医学遗传学分册, 2001, 24(1): 24-27.
1. Kharbanda S, Saleem A, Shafman T, et al. Activation of the pp90rsk and mitogen-activated serine/threonine protein kinase by ionizing radiation. Proc Natl Acad Sci USA, 1994, 91(12): 5416-5420.
2. Sukhotnik I, Shteinberg D, Ben Lulu S, et al. Transforming growth factor-alpha stimulates enterocyte proliferation and accelerates intestinal recovery following methotrexate-induced intestinal mucositis in a rat and a cell culture model. Pediatr Surg Int, 2008, 24(12):1303-1311.
3. Edelblum KL, Washington MK, Koyama T, et al. Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB. Gastroenterology, 2008,135(2):539-551.
4. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
5. Tenney R, Stansfield K, Pekala PH. Interleukin 11 signaling in 3T3-L1 adipocytes. J Cell Physiol, 2005 , 202(1):160-166.
6. Duplomb L, Chaigne-Delalande B, Vusio P, et al. Soluble mannose 6-phosphate/insulin-like growth factor II (IGF-II) receptor inhibits interleukin-6-type cytokine-dependent proliferation by neutralization of IGF-II. Endocrinology, 2003, 144(12):5381-5389.
7. Luongo D, Mazzarella G, Della RF, et al. Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29. Mol Cell Biochem, 2002, 231(1-2):43-50.
8. Taupin D, Podolsky DK. Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology, 1999, 116(5):1072-1080.
9. Dieckgraefe BK, Weems DM. Epithelial injury induces egr-1 and fos expression by a pathway involving protein kinase C and ERK. Am J Physiol, 1999, 276(21):322-330.
10.郑曙云,付小兵,徐建国. MAPK信号传导通路与肠损伤后黏膜上皮修复.中国危重病急救医学, 2004, 16(1): 59-62.
11. van der Wijk T, Dorrestijn J, Narumiya S, et al. Osmotic swelling-induced activation of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2 in intestine 407 cells involves the Ras/Raf-signalling pathway. Biochem J, 1998, 331 (3):863-869.
12. Kim CS, Kim JK, Nam SY, et al. Low-dose radiation stimulates the proliferation of normal human lung fibroblasts via a transient activation of Raf and Akt. Mol Cells, 2007, 24(3):424-430.
13. Casarez EV, Dunlap-Brown ME, Conaway MR, et al. Radiosensitization and modulation of p44/42 mitogen-activated protein kinase by 2-Methoxyestradiol in prostate cancer models. Cancer Res, 2007, 67(17):8316-8324.
14. Kumar P, Coltas IK, Kumar B, et al. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
15. Yacoub A, Park JS, Qiao L, et al. MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 2001, 77(10):1067-1078.
16. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
17.左红艳.不同频段电磁辐射致大鼠海马损伤效应及蛋白质组学研究.军事医学科学院博士学位论文, 2007.
18.周舟,王小华, Igisu Hideki,等.辐射诱导IEC-6细胞MAPK信号转导途径的激活.辐射研究与辐射工艺学报, 2002, 20(2): 137-145.
19. Lee S, Fang L, Igarashi M, et al. Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53. Proc Natl Acad Sci USA, 2000, 97, 8302?8305.
20. Golding SE, Rosenberg E, Neill S, et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res, 2007, 67(3):1046-53.
21. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int J Oncol, 2006, 29(1):163-168.
22. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
23. Naugler KM, Baer KA, Ropeleski MJ. Interleukin-11 antagonizes Fas ligand-mediated apoptosis in IEC-18 intestinal epithelial crypt cells: role of MEK and Akt-dependent signaling. Am J Physiol Gastrointest Liver Physiol, 2008, 294(3): 728-737.
24. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
25. Golding SE, Rosenberg E, Neill S, et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res, 2007, 67(3):104610-104653.
26. MacLaine NJ, Wood MD, Holder JC, et al. Sensitivity of normal, paramalignant, and malignant human urothelial cells to inhibitors of the epidermal growth factor receptor signaling pathway. Mol Cancer Res, 2008, 6(1):53-63.
27. Hamed H, Hawkins W, Mitchell C, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo. Mol Cancer Ther, 2008, 7(3):616-629.
28. Liao YH, Hsu SM, Huang PH. ARMS depletion facilitates UV irradiation induced apoptotic cell death in melanoma. Cancer Res, 2007, 67(24):11547-11556.
29. Kim BY, Kim KA, Kwon O, et al. NF-kappa B inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation. Carcinogenesis, 2005, 26(8):1395-1403.
30. Hagan MP, Yacoub A, Dent P. Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. J Cell Biochem, 2007, 101(6):1384-1393.
31. Yacoub A, Miller A, Caron RW,et al. Radiotherapy-induced signal transduction. Endocr Relat Cancer, 2006, 13 Suppl 1:S99-114.
32. Sheng H, Shao J, Townsend CM J, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
1.薛景,刘芬菊. PI3K/Akt与胶质瘤辐射抗性.国外医学.放射医学核医学分册, 2005, 29(1): 40-43.
2. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kB transcription factors. Oncogene, 1999, 18(49): 6910-6924.
3. Roche S, Downward J, Raynal P, et al. A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction, Mol Cell Biol, 1998, 18:7119–7129.
4. Sheng H, Shao J, Townsend CM J, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
5. Huet C, Sahuquillo-Merino C, Coudrier E, et al. Absorptive and mucussecreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation. J Cell Biol, 1987, 105:345-357.
6. Shao J, Evers BM, Sheng H. Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res, 2004, 64(1):229-235.
7. Tamura T, Cui X, Sakaguchi N, et al. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol, 2008, 46(9):3080-3089.
8. Greenspon J, Li R, Xiao L, et al. Sphingosine-1-phosphate protects intestinal epithelial cells from apoptosis through the Akt signaling pathway. Dig Dis Sci, 2009, 54(3):499-510.
9. Uemura T, Nakayama T, Kusaba T, et al.The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
10.田梅,朴春姬,李修义,等. IR诱导pEgr-hPTEN表达增强其体外抗肿瘤作用.吉林大学学报(医学版), 2005, 31(3): 330-333.
11. Montgomery RK, Breault DT. Small intestinal stem cell markers. J Anat, 2008, 213(1):52-8.
12. Wang Q, Zhou Y, Wang X, et al. Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. Cancer Res, 2007, 67(16):7773-7781.
13. G·克劳斯著,孙超,刘景生,王子镐,等译.信号转导与调控的生物化学.北京,化学工业出版社,第三版, 2005.187-395.
14. Wang ML, Keilbaugh SA, Cash-Mason T, et al. Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways. Am J Physiol Gastrointest Liver Physiol, 2008, 295(5): 1122-1130.
15. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
16. Uemura T, Nakayama T, Kusaba T, et al. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
17. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
18. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
19. Fuhrer DK, Yang YC. Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11. Exp Hematol, 1996, 24(2):195-203.
20. Nakayama T, Yoshizaki A, Izumida S, et al. Expression of interleukin-11 (IL-11) and IL-11 receptor alpha in human gastric carcinoma and IL-11 upregulates the invasive activity of human gastric carcinoma cells. Int J Oncol, 2007, 30(4):825-833.
21. Oka N, Tanimoto S, Taue R, et al. Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci, 2006, 97(10):1093-1098.
22. Krystal GW, Sulanke G, Litz J. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. Mol Cancer Ther, 2002, 1(11):913-922.
23. Hagan MP, Yacoub A, Dent P. Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. J Cell Biochem, 2007, 101(6):1384-1393.
24. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
1. Shelton JG, Steelman LS, White ER, et al. Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle, 2004, 3(3):372-379.
2. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2):189-218.
3.袁向飞,陆敏. Ras/MAPK与PI3K/Akt信号转导通路及其相互作用.国际检验医学杂志, 2006, 27(3): 261-263.
4. G·克劳斯著,孙超,刘景生,王子镐,等译.信号转导与调控的生物化学.化学工业出版社,第三版, 2005.187-189.
5. Menges CW, McCance DJ. Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor. Oncogene, 2008, 27(20):2934-2940.
6. Marino M, Acconcia F, Trentalance A. Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell, 2003, 14(6):2583-2591.
7. López-Pedrera C, Barbarroja N, Buendía P, et al. Promyelocytic leukemia retinoid signaling targets regulate apoptosis, tissue factor and thrombomodulin expression. Haematologica, 2004, 89(3):286-295.
8. Yamboliev IA, Wiesmann KM, Singer CA, et al. Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle. Am J Physiol Cell Physiol, 2000, 279(2): 352-360.
9. Schmidt EK, Fichelson S, Feller SM. PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors. BMC Biol, 2004,2:7.
10. Wang CC, Cirit M, Haugh JM. PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk. Mol Syst Biol, 2009, 5:246.
11. Lee MY, Jo SD, Lee JH, et al. L-leucine increases [3H]-thymidine incorporation in chicken hepatocytes: involvement of the PKC, PI3K/Akt, ERK1/2, and mTOR signaling pathways. J Cell Biochem, 2008, 105(6):1410-1419.
12. Campbell M, Allen WE, Sawyer C, et al. Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res, 2004, 95(4):380-388.
13. Levinthal DJ, DeFranco DB. Transient phosphatidylinositol 3-kinase inhibition protects immature primary cortical neurons from oxidative toxicity via suppression of extracellular signal-regulated kinase activation. J Biol Chem, 2004, 279(12):11206-11213.
14. Campbell M, Allen WE, Sawyer C, et al. Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res, 2004, 95(4):380-388.
15. Kim YM, Namkoong S, Yun YG, et al. Water extract of Korean red ginseng stimulatesangiogenesis by activating the PI3K/Akt-dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells. Biol Pharm Bull, 2007, 30(9):1674-1679.
16. Bradley EW, Ruan MM, Vrable A, et al. Pathway crosstalk between Ras/Raf and PI3K in promotion of M-CSF-induced MEK/ERK-mediated osteoclast survival. J Cell Biochem, 2008, 104(4):1439-1451.
17. Lee JT Jr, Steelman LS, Chappell WH, et al. Akt inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells. Cell Cycle, 2008, 7(5):631-636.
18. Gervais M, Dugourd C, Muller L, et al. Akt down-regulates ERK1/2 nuclear localization and angiotensin II-induced cell proliferation through PEA-15. Mol Biol Cell, 2006, 17(9):3940-3951.
19. Hatakeyama M, Kimura S, Naka T, et al. A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. Biochem J, 2003, 373(Pt 2):451-463.
20. Dai R, Chen R, Li H. Cross-talk between PI3K/Akt and MEK/ERK pathways mediates endoplasmic reticulum stress-induced cell cycle progression and cell death in human hepatocellular carcinoma cells. Int J Oncol, 2009, 34(6):1749-1757.
21. Bouali S, Chrétien AS, Ramacci C, et al. PTEN expression controls cellular response to cetuximab by mediating PI3K/AKT and RAS/RAF/MAPK downstream signaling in KRAS wild-type, hormone refractory prostate cancer cells. Oncol Rep, 2009, 21(3):731-735.
22. He S, Dibas A, Yorio T, et al. Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells. Exp Biol Med (Maywood), 2007, 232(3):370-384.
23. Romano D, Pertuit M, Rasolonjanahary R, et al. Regulation of the RAP1/RAF-1/extracellularly regulated kinase-1/2 cascade and prolactin release by the phosphoinositide 3-kinase/AKT pathway in pituitary cells. Endocrinology, 2006, 147(12):6036-6045.
24. Liu L, Xie Y, Lou L. PI3K is required for insulin-stimulated but not EGF-stimulated ERK1/2 activation. Eur J Cell Biol, 2006, 85(5):367-374.
1. Brown M. What causes the radiation gastrointestinal syndrome: overview. Int J Radiat Oncol Biol Phys, 2008, 70(3): 799-800.
2. Potten CS, Wilson JW, Booth C. Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells, 1997, 15(2):82-93.
3. Harnois C, Demers MJ, Bouchard V, et al. Human intestinal epithelial crypt cell survival and death: Complex modulations of Bcl-2 homologs by Fak, PI3-K/Akt-1, MEK/Erk, and p38 signaling pathways. J Cell Physiol, 2004, 198(2):209-222.
4. Kumar P, Coltas IK, Kumar B, et al. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
5.弓清梅,李建强,刘卓拉.大鼠急性肺损伤过程中STAT3的活化对bcl-2/ bax表达及细胞凋亡的影响.中国药物与临床, 2007, (7)1: 35-37.
6. Tamura T, Cui X, Sakaguchi N, et al. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol, 2008, 46(9):3080-3089.
7. Matsuu-Matsuyama M, Shichijo K, Okaichi K, et al. Sucralfate protects intestinal epithelial cells from radiation-induced apoptosis in rats. J Radiat Res (Tokyo), 2006, 47(1):1-8.
8. Park E, Lee NH, Joo HG, et al. Modulation of apoptosis of eckol against ionizing radiation in mice. Biochem Biophys Res Commun, 2008, 372(4):792-797.
9. Matsuu-Matsuyama M, Shichijo K, Okaichi K, et al. Protection by polaprezinc against radiation-induced apoptosis in rat jejunal crypt cells. J Radiat Res (Tokyo), 2008, 49(4):341-347.
10. Watson AJ, Pritchard DM. Lessons from genetically engineered animal models. VII. Apoptosis in intestinal epithelium: lessons from transgenic and knockout mice. Am J Physiol Gastrointest Liver Physiol, 2000, 278(1):G1-5.
11. Shaposhnikov Y, Maheshwari Y, Sykes DE, et al. Intestinal cell apoptosis and Bcl-2 expression. Cell Death Differ, 1996, 3(1):125-130.
12. Pritchard DM, Potten CS, Korsmeyer SJ, et al. Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene, 1999, 18(51):7287-7293.
13. Coopersmith CM, O'Donnell D, Gordon JI. Bcl-2 inhibits ischemia-reperfusion-induced apoptosis in the intestinal epithelium of transgenic mice. Am J Physiol, 1999, 276(3 Pt 1):G677-686.
14. Duckworth CA, Pritchard DM. Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice. Gastroenterology, 2009, 136(3):943-952.
15. Hendry JH, Broadbent DA, Roberts SA, et al. Effects of deficiency in p53 or bcl-2 on the sensitivity of clonogenic cells in the small intestine to low dose-rate irradiation. Int J Radiat Biol. 2000, 76(4):559-565.
16. Van Houten N, Blake SF, Li EJ, et al. Elevated expression of Bcl-2 and Bcl-x by intestinal intraepithelial lymphocytes: resistance to apoptosis by glucocorticoids and irradiation. Int Immunol, 1997, 9(7):945-953.
17. Tessner TG, Muhale F, Riehl TE, et al. Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation. J Clin Invest, 2004, 114(11):1676-1685.
18. G·克劳斯著,孙超,刘景生,等译.信号转导与调控的生物化学.第三版, 2005, 394-395.
19. Gui C, Wang JA, He AN, et al. Heregulin protects mesenchymal stem cells from serum deprivation and hypoxia-induced apoptosis. Mol Cell Biochem, 2007, 305(1-2):171-178.
20. Li CR, Zhou Z, Zhu D, et al. Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. Int J Biochem Cell Biol, 2007, 39(2):426-438.
21. Li LH, Wu LJ, Tashiro SI, et al. The roles of Akt and MAPK family members in silymarin's protection against UV-induced A375-S2 cell apoptosis. Int Immunopharmacol, 2006, 6(2):190-197.
1.毛秉智,陈家佩,主编.急性放射病基础与临床.北京:军事医学科学出版社,第一版, 2002.
2. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17(14):1709-1713.
3. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell, 2005, 97(3): 185-196.
4. Ouko L, Ziegler TR, Gu LH, et al. Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem, 2004, 279(25): 26707-26715.
5. Pinto D, Clevers H. Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res, 2005, 306(2):357-363.
6.梅文燕,丁小燕. Wnt信号途径及其作用机制.生命的化学, 2000, 20(5): 193-197.
7. Ogasawara N, Tsukamoto T, Mizoshita T, Inada K, Cao X, Takenaka Y, Joh T, Tatematsu M. Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human gastric cancer. Histopathology,2006, 49(6):612-621.
8.姜祖韵,袁毅君,明镇寰,等.维持胚胎干细胞自我更新分子机制的研究进展.生物化学与生物物理进展, 2004, 31(11): 965-968.
9.王启明,杨开明,周鸿鹰,等.β-catenin在大鼠胚胎肝脏发育和肝癌发生中的作用.四川大学学报(医学版), 2006, 37(6):872-875.
10.林琼琼,李锦添,王敏. Wnt通路中APC、β-catenin及c-myc与大肠癌的关系.广西医学, 2006, 28(2): 233-235.
11. Fujimura N, Vacik T, Machon O, et al. Wnt-mediated down-regulation of Sp1 target genes by a transcriptional repressor Sp5. J Biol Chem, 2007, 282(2):1225-1237.
12.殷河慧,廖文俊. Wnt信号转导通路及其在皮肤肿瘤中的作用.国外医学皮肤性病学分册, 2005, 31(2):119-121.
13.黄勇,窦科峰.β-连环蛋白在原发性肝细胞癌中的表达及其临床意义.第四军医大学学报, 2002, 23(12): 1103-1105.
14. Batlle E, Henderson JT, Beghtel H, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell, 2002, 111(2):251-263.
15. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev, 2003, 17(14):1709-1713.
16. Pinto D, Clevers H. Wnt, stem cells and cancer in the intestine. Biol Cell, 2005, 97(3):185-196.
17. Ouko L, Ziegler TR, Gu LH, et al. Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem, 2004, 279(25):26707-26715.
18. Wong MH, Huelsken J, Birchmeier W, et al. Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkuhn is perturbed by stimulation of Lef-1/beta-catenin signaling. J Biol Chem, 2002, 277(18):15843-15850.
19. Mariadason JM, Bordonaro M, Aslam F, et al. Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res, 2001, 61(8):3465-3471.
20. Horn K, Batlle E, Coudreuse D, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell, 2002, 111(2):241-250.
21. Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol, 2007 Feb 15; [Epub ahead of print]
22. Wong MH, Rubinfeld B, Gordon JI. Effects of forced expression of an NH2-terminal truncated beta-Catenin on mouse intestinal epithelial homeostasis. J Cell Biol, 1998, 141(3):765-777.
23. Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet, 1998, 19(4):379-383.
24. Muncan V, Sansom OJ, Tertoolen L, et al. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol Cell Biol, 2006, 26(22):8418-8426.
25. Hao X, Tomlinson I, Ilyas M, et al. Reciprocity between membranous and nuclear expression of beta-catenin in colorectal tumours. Virchows Arch, 1997, 431(3):167-172.
26. Murata M, Iwao K, Miyoshi Y, et al. Molecular and biological analysis of carcinoma of thesmall intestine: beta-catenin gene mutation by interstitial deletion involving exon 3 and replication error phenotype. Am J Gastroenterol, 2000, 95(6):1576-1580.
27. Iwamoto M, Ahnen DJ, Franklin WA, et al. Expression of beta-catenin and full-length APC protein in normal and neoplastic colonic tissues. Carcinogenesis, 2000, 21(11):1935-1940.
28. Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science, 1997, 275(5307):1784-1787.
29. Van der Flier LG, Sabates-Bellver J, Oving I, et al. The Intestinal Wnt/TCF Signature. Gastroenterology, 2007, 132(2):628-632.
30. Mariadason JM, Bordonaro M, Aslam F, et al.Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res, 2001, 61(8):3465-3471.
31. Mei JM, Hord NG, Winterstein DF, et al. Differential formation of beta-catenin/lymphoid enhancer factor-1 DNA binding complex induced by nitric oxide in mouse colonic epithelial cells differing in adenomatous polyposis coli (Apc) genotype. Cancer Res, 2000, 60(13):3379-3383.
32. Mezhybovska M, Wikstrom K, Ohd JF, et al. The inflammatory mediator leukotriene D4 induces beta-catenin signaling and its association with antiapoptotic Bcl-2 in intestinal epithelial cells. J Biol Chem, 2006, 281(10):6776-6684.
33. Kucharczak J, Simmons MJ, Fan Y, et al.To be, or not to be: NF-κB is the answer-role of Rel/NF-κB in the regulation of apoptosis. Oncogene, 2003, 22(56):8961-8982.
34. Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death-a new approach to cancer therapy. J Clin Invest, 2005, 115(10): 2625-2632.
35. Karrasch T, Jobin C. NF-kappaB and the intestine: friend or foe? Inflamm Bowel Dis, 2008, 14(1):114-124.
36. Chen F, Castranova V, Shi X. New Insights into the Role of Nuclear Factor-κB in Cell Growth Regulation. Am J Pathol, 2001, 159(2):387-397.
37. Dajani R, Sanlioglu S, Zhang Y, et al. Pleiotropic functions of TNF-alpha determine distinct IKKbeta-dependent hepatocellular fates in response to LPS. Am J Physiol Gastrointest Liver Physiol, 2007, 292(1):G242-252.
38. Grana TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
39. Wang Y, Meng A, Lang H, et al. Activation of nuclear factor kappaB in vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res, 2004, 64(17):6240-6246.
40. Egan LJ, Eckmann L, Greten FR, et al. IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proc Natl Acad Sci USA, 2004, 101(8):2452-2457.
41. Peng Z, Peng L, Fan Y, et al. A critical role for IkappaB kinase beta in metallothionein-1 expression and protection against arsenic toxicity. J Biol Chem, 2007, 282(29):21487-21496.
42. Zaph C, Troy AE, Taylor BC, et al. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature, 2007, 446(7135):552-556
43.薛景,刘芬菊. PI3K/Akt与胶质瘤辐射抗性.国外医学.放射医学核医学分册, 2005, 29(1): 40-43.
44. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kB transcription factors. Oncogene, 1999, 18(49): 6910-6924.
45. Roche S, Downward J, Raynal P, et al. A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction, Mol Cell Biol, 1998, 18:7119–7129.
46. Sheng H, Shao J, Townsend CM Jr, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut, 2003, 52(10):1472-1478.
47. Huet C, Sahuquillo-Merino C, Coudrier E, et al. Absorptive and mucussecreting subclones isolated from a multipotent intestinal cell line (HT-29) provide new models for cell polarity and terminal differentiation. J Cell Biol, 1987, 105:345-357.
48. Shao J, Evers BM, Sheng H. Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res, 2004, 64(1):229-235.
49. Tamura T, Cui X, Sakaguchi N,et al. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol, 2008, 46(9):3080-3089.
50. Greenspon J, Li R, Xiao L, et al. Sphingosine-1-phosphate protects intestinal epithelial cells from apoptosis through the Akt signaling pathway. Dig Dis Sci, 2009, 54(3):499-510.
51. Uemura T, Nakayama T, Kusaba T, et al. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
52. G·克劳斯著,孙超,刘景生,王子镐,等译.信号转导与调控的生物化学.北京,化学工业出版社,第三版, 2005.187-395.
53. Wang ML, Keilbaugh SA, Cash-Mason T, et al. Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways. Am J Physiol Gastrointest Liver Physiol, 2008, 295(5): 1122-1130.
54. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
55. Uemura T, Nakayama T, Kusaba T, et al. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J Radiat Res (Tokyo), 2007, 48(2):171-177.
56. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-76.
57. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
58. Fuhrer DK, Yang YC. Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11. Exp Hematol, 1996, 24(2):195-203.
59. Kharbanda S, Saleem A, Shafman T, et al. Activation of the pp90rsk and mitogen-activated serine/threonine protein kinase by ionizing radiation. Proc Natl Acad Sci USA, 1994, 91(12): 5416-5420.
60. Sukhotnik I, Shteinberg D, Ben Lulu S, et al. Transforming growth factor-alpha stimulates enterocyte proliferation and accelerates intestinal recovery following methotrexate-induced intestinal mucositis in a rat and a cell culture model. Pediatr Surg Int, 2008, 24(12):1303-1311.
61. Edelblum KL, Washington MK, Koyama T, et al. Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB. Gastroenterology, 2008, 135(2):539-551.
62. Luongo D, Mazzarella G, Della RF, et al. Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29. Mol Cell Biochem, 2002, 231(1-2):43-50.
63. Taupin D, Podolsky DK. Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology, 1999, 116(5):1072-1080.
64. Dieckgraefe BK, Weems DM. Epithelial injury induces egr-1 and fos expression by a pathway involving protein kinase C and ERK. Am J Physiol, 1999, 276(21):322-330.
65.郑曙云,付小兵,徐建国. MAPK信号传导通路与肠损伤后黏膜上皮修复.中国危重病急救医学, 2004, 16(1): 59-62.
66. Kumar P, Coltas IK, Kumar B, et alJ. Bcl-2 protects endothelial cells against gamma-radiation via a Raf-MEK-ERK-survivin signaling pathway that is independent of cytochrome c release. Cancer Res, 2007, 67(3):1193-1202.
67. van der Wijk T, Dorrestijn J, Narumiya S, et al. Osmotic swelling-induced activation of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2 in intestine 407 cells involves the Ras/Raf-signalling pathway. Biochem J, 1998, 331 (3):863-869.
68. Yacoub A, Park JS, Qiao L, et al. MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 2001, 77(10):1067-1078.
69. Grana TM, Rusyn EV, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Cancer Res, 2002, 62(14):4142-4150.
70.左红艳.不同频段电磁辐射致大鼠海马损伤效应及蛋白质组学研究.军事医学科学院博士学位论文, 2007.
71.周舟,王小华, Igisu Hideki,等.辐射诱导IEC-6细胞MAPK信号转导途径的激活.辐射研究与辐射工艺学报, 2002, 20(2): 137-145.
72. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int J Oncol, 2006, 29(1):163-168.
73. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem, 2004, 279(11):10304-10315.
74. Naugler KM, Baer KA, Ropeleski MJ. Interleukin-11 antagonizes Fas ligand-mediated apoptosis in IEC-18 intestinal epithelial crypt cells: role of MEK and Akt-dependent signaling. Am J Physiol Gastrointest Liver Physiol, 2008, 294(3): 728-737.
75. Yoshizaki A, Nakayama T, Yamazumi K, et al. Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive andproliferative activity of human colorectal carcinoma cells. Int J Oncol, 2006, 29(4):869-876.
76.宋伦,沈倍奋. Jak/STAT信号转导途径研究新进展.免疫学杂志, 2000, 16(1): 68-71.
77. Heinrich PC, Behrmann I, Muller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J, 1998, 334 ( Pt 2): 297-314.
78. Gao H, Guo RF, Speyer CL, et al. Stat3 activation in acute lung injury. J Immunol, 2004, 172(12):7703-7712.
79. Tebbutt NC, Giraud AS, Inglese M, et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med, 2002, 8(10):1089-1097.
80. Musso A, Dentelli P, Carlino A, et al. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis, 2005, 11(2):91-98.
81. Mudter J, Weigmann B, Bartsch B, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol, 2005, 100(1):64-72.
82. Alonzi T, Newton IP, Bryce PJ, et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine, 2004, 26(2):45-56.
83. Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci USA, 2003, 100(4):1879-1884.
84. Zushi S, Shinomura Y, Kiyohara T, et al. STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer, 1998, 78(3):326-330.
85. Kiessling S, Muller-Newen G, Leeb SN, et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem. 2004, 279(11):10304-10315.
86. Ropeleski MJ, Tang J, Walsh-Reitz MM, et al. Interleukin-11-induced heat shock protein 25 confers intestinal epithelial-specific cytoprotection from oxidant stress. Gastroenterology, 2003, 124(5):1358-1368.
87. Shelton JG, Steelman LS, White ER, et al. Synergy between PI3K/Akt and Raf/MEK/ERK pathways in IGF-1R mediated cell cycle progression and prevention of apoptosis in hematopoietic cells. Cell Cycle, 2004, 3(3):372-379.
88. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2):189-218.
89. Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2): 189-218.