JAK-STATs通路对CTGF刺激人增生性瘢痕成纤维细胞增殖分化作用的研究
|
摘要
增生性瘢痕是烧伤、整形乃至整个创伤修复领域亟待解决的难题之一,成纤维细胞是其发病的关键效应细胞,生长因子对成纤维细胞的增殖、分化具有重要的调控作用。结缔组织生长因子(CTGF)是新近发现的一种具有强烈促纤维化作用的生长因子,有研究证实[1],CTGF能促进体外增生性瘢痕成纤维细胞(HSF)增殖及其向肌成纤维细胞(MyoF)的转分化,但其细胞内信号转导机制尚不清楚,未见相关报道。JAK-STATs通路是近几年发现的细胞因子信息内传的非常重要的一条通路,是参与人体内部分生理(如造血)和病理反应(如部分肿瘤、类风湿性关节炎、脑损伤、支气管哮喘等)的共同通路之一,已证实与多种疾病发生发展及防治密切相关[2-5]。目前已知有多种细胞因子(如干扰素-α、β、γ,白细胞介素-2、4、6等)、生长因子(表皮生长因子、血小板衍生生长因子等)、生长激素、瘦素等通过JAK-STATs途径进行信号转导并调控部分细胞的增殖分化过程。鉴于以上原因,我们选择其作为参与CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的信号通路进行筛选鉴定。
方法:
本研究通过原代培养人增生性瘢痕成纤维细胞,将对象分为①对照组:人增生性瘢痕成纤维细胞组;②CTGF刺激人增生性瘢痕成纤维细胞组。采用Western blot、免疫荧光化学染色、凝胶阻滞电泳(EMSA)、RT-PCR方法,分以下两大部分进行研究,第一大部分为JAK-STATs信号分子的初步筛选,包括①取0min、5 min、10 min、20 min、30 min、45 min、60 min、90 min八个时相点,采用western-blot方法检测各时相点JAK1、JAK2、JAK3、TYK2、STAT1、STAT2、STAT3、STAT4、STAT5、STAT6十类蛋白活化(磷酸化)情况,并筛选出对CTGF刺激其磷酸化程度呈反应性增高的蛋白(JAK1、STAT1);②对筛选出来的蛋白(STAT1)用免疫荧光化学染色方法观察其胞浆到胞核的核转位的时相变化并比较组间差异;③利用凝胶阻滞电泳(EMSA)方法进一步验证此蛋白(STAT1)与DNA的结合能力及持续时间。第二大部分,将对象分为四组:①STAT1 ASODN+CTGF组;②CTGF刺激组;③STAT1 ASODN转染组;④空白对照组。在上述研究基础上,对筛选出的信号分子(STAT1)应用特异性抑制剂(STAT1 ASODN)进行阻断,用MTT法测定各组间细胞增殖差异, RT-PCR观察α-SMA的表达以反映人增生性瘢痕成纤维细胞向肌成纤维细胞转分化情况,以了解STAT1对CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的影响。
结果:
CTGF刺激人增生性瘢痕成纤维细胞后JAK-STATs通路所有蛋白(总蛋白以“t-”表示)均以非磷酸化和磷酸化(以“p-”表示)两种形式存在,在起始状态下即出现磷酸化条带,之后其磷酸化程度逐渐增强,在30min左右达峰值,再随时间延长逐渐下降呈一倒抛物线。Western blot显示胞浆及胞核中“p-JAK1/ t-JAK1”比值和“p-STAT1/ t-STAT1”比值随CTGF作用时间延长逐渐增大,至30min时达最强,之后逐渐下降。其余JAK-STATs蛋白虽均有不同程度的磷酸化,但并未随CTGF刺激出现反应性增强趋势。应用免疫荧光化学染色法检测STAT1的核转位,发现磷酸化STAT1蛋白在刺激30min左右达最强,比较组间差异发现:瘢痕成纤维细胞组(++):荧光明亮,胞浆、胞核分布基本一致;CTGF刺激瘢痕成纤维细胞组(+++-++++):荧光闪亮,呈明显的亮绿色,胞核中荧光强度增加,核聚集现象明显;应用凝胶阻滞电泳法,采用不同浓度CTGF刺激时发现检测STAT1与DNA的结合能力呈CTGF浓度依赖趋势,当CTGF 10ng/ml时达到峰值。同时,我们用10ng/ml CTGF刺激人增生性瘢痕成纤维细胞在不同时相点(0、10、20、30、45、60、90、120min)STAT1与DNA的结合能力及持续时间时发现:当CTGF刺激10min时,SIF已开始活化,45-60min达峰值,之后逐渐减弱,且较对照组明显增强。根据以上结果,初步筛选出JAK1、STAT1蛋白为参与CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的信号分子。
为进一步验证上述结论,我们将对象分为四组:①STAT1 ASODN+CTGF组;②CTGF刺激组;③STAT1 ASODN转染组;④空白对照组,观察STAT1对CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的影响。在RT-PCR确定STAT1 ASODN已成功转入的前提下,用MTT测定转染前后细胞增殖程度变化时发现,增生性瘢痕成纤维细胞增殖程度呈②>④>①③的趋势变化,转染后细胞增殖明显受到抑制,结果具有统计学意义(P<0.05)。同时,我们采用RT-PCR比较转染前后a-SMA的差异,发现转染前后a-SMA/GAPDH条带灰度值无明显差异(P>0.05),结果不具有统计学意义。
结论:
1、在CTGF促进人增生性瘢痕成纤维细胞增殖与转分化的同时,JAK1和STAT1蛋白被不同程度活化,其活化程度随CTGF的刺激反应性增强,胞核中磷酸化STAT1荧光强度明显增加,核聚集现象明显;STAT1与DNA的结合能力增强。
2、STAT1 ASODN转染后人增生性瘢痕成纤维细胞增殖能力明显下降,但并未完全抑制其增殖过程;
3、STAT1 ASODN转染后人增生性瘢痕成纤维细胞向肌成纤维细胞的转分化能力则未见明显改变。
以上研究结果提示:STAT1参与了CTGF调控人增生性瘢痕成纤维细胞增殖过程,但并非是唯一途径;而JAK1则可能作为其上游因子,通过JAK1-STAT1通路参与了CTGF促进人增生性瘢痕成纤维细胞增殖过程。这从一定程度上揭示了CTGF调控人增生性瘢痕成纤维细胞增殖过程的信号转导机制,从而为抑制瘢痕纤维化提供了新的研究方向,有助于更深入地调控CTGF的促纤维化作用,为增生性瘢痕及其它纤维化疾病的研究及防治提供新的思路。
Hypertrophic scar is a quiz which needs to be solved in burn surgery.plastic surgery and all the trauma field.as the key effector cell,fibroblast is regulated by growth factor in the aspect of proliferation and differentiation.Connective tissue growth factor(CTGF) is a kind of fator which can promote fibrosis intensively and urge vitro-human hypertrophic scar fibroblast to differentiate to myofibroblast[1].But there is rare reports to its signal transduction mechanism.JAK-STATs pathway is a very important one which is found in recent years and play a part in cytokine signal transduction,and it paticipates in many physiological functions(eg. haematogenesis)and patho-functions(eg. Tumor.arthritis deformans.brain injured.bronchial asthma) [2-5].A lot of cytokines(eg. Interferon-α.β.γ, interleukin-2.4.6) .growth factors(eg. epidermal growth factor.platelet-derived growth factor) .growth hormone.leptin regulate proliferation and differentiation of many cells through JAK-STATs.Respecting the aboved reasons,we carry out the work to study the function of JAK-STATs pathway in proliferation and differentiation of human hypertrophic scar fibroblast induced by connective tissue growth factor.
Methods: cultivate hHSF with primary cultivation,then, divide the cells into two groups:①control group:hHSF②CTGF-stimulated group:hHSF with CTGF.The 1st part included:①Western-blot was used to detect proteins’activation including JAK1.JAK2.JAK3.TYK2.STAT1.STAT2.STAT3.STAT4.STAT5.STAT6 at 0min.5 min.10 min.20 min.30 min.45 min.60 min.90 min .②Immunofluorescence(IF)was used to verify nuclear translocation of the boltered protein.③Electrophoretic mobility shift assay(EMSA) was used to verify binding ability with DNA of the boltered protein.In the 2nd part,we divided cells into four groups:①STAT1 ASODN+CTGF group;②CTGF group;③STAT1 ASODN group;④control group.And then,we used MTT to detect the proliferation of hHSF and western-blot to detectα-SMA to learn the differentiation .
Results: In the premise that proliferation and differentiation of CTGF-stimulated group was much higher than that of control group(p<0.05),results of western-blot showed all the JAK-STATs proteins(“t-”) exists in two styles:non-phosphorylation and phosphorylation(“p-”).The phosphorylated protein appears at the beginnning,and then increased gradually,peaked at 30min,and fell-off afer 30mins.Among all the proteins ,only the ratio of“p-JAK1/ t-JAK1”and“p-STAT1/ t-STAT1”increased following CTGF stimulation. IF results showed phosphorylated STAT1 peaked at 30min.We compared the two groups and found:①control group(++):bright,flavo-green;②CTGF group(+++-++++): blink,obviouse bright green. EMSA told us that the binding ability of STAT1 and DNA depended on the concentration of CTGF,and peaked with the stimulation of 10ng/ml CTGF.And then,we used 10 ng/ml CTGF to stimulate hHSF at 0.10.20.30.45.60.90.120min and found that SIF was activated at 10min,peaked at 45-60min,fell-off gradully after 60min.The binding ability of CTGF group was much higher than that of control group.So JAK1.STAT1 was selected in preliminary screening.
And then ,we used STAT1 ASODN to block the STAT1.In the premise of sucessful transfection of STAT1 ASODN by RT-PCR,we found that the proliferation of hHSF was inhibited obviously with MTT afer ASODN transfection(P<0.05),but expression ofα-SMA changed little before and after the blockage of STAT1 ASODN(P>0.05). Conclusions:
1. At the same time of CTGF-stimulated proliferation and differentiation of hHSF,JAK1and STAT1was activated to some extent,and increased following CTGF stimulation.And fluorescence intensity of phosphorylated STAT1 and binding ability of STAT1and DNA increased obviously following the activation of CTGF;
2. The proliferation of hHSF was inhibited obviously but not all with MTT afer ASODN transfection(P<0.05);
3. Expression ofα-SMA changed little before and after the blockage of STAT1 ASODN(P>0.05).
STAT1 is important in the process of CTGF-induced proliferation of hHSF,but it’s not the only pathway to control the process.JAK1 may be the upstream element of STAT1 and may paticipate in the process of CTGF-induced proliferation of hHSF.The results above revealed the signal transduction mechanism of CTGF-induced proliferation of hHSF ,may afford new direction to inhibit scar fibrosis and contraction.
方法:
本研究通过原代培养人增生性瘢痕成纤维细胞,将对象分为①对照组:人增生性瘢痕成纤维细胞组;②CTGF刺激人增生性瘢痕成纤维细胞组。采用Western blot、免疫荧光化学染色、凝胶阻滞电泳(EMSA)、RT-PCR方法,分以下两大部分进行研究,第一大部分为JAK-STATs信号分子的初步筛选,包括①取0min、5 min、10 min、20 min、30 min、45 min、60 min、90 min八个时相点,采用western-blot方法检测各时相点JAK1、JAK2、JAK3、TYK2、STAT1、STAT2、STAT3、STAT4、STAT5、STAT6十类蛋白活化(磷酸化)情况,并筛选出对CTGF刺激其磷酸化程度呈反应性增高的蛋白(JAK1、STAT1);②对筛选出来的蛋白(STAT1)用免疫荧光化学染色方法观察其胞浆到胞核的核转位的时相变化并比较组间差异;③利用凝胶阻滞电泳(EMSA)方法进一步验证此蛋白(STAT1)与DNA的结合能力及持续时间。第二大部分,将对象分为四组:①STAT1 ASODN+CTGF组;②CTGF刺激组;③STAT1 ASODN转染组;④空白对照组。在上述研究基础上,对筛选出的信号分子(STAT1)应用特异性抑制剂(STAT1 ASODN)进行阻断,用MTT法测定各组间细胞增殖差异, RT-PCR观察α-SMA的表达以反映人增生性瘢痕成纤维细胞向肌成纤维细胞转分化情况,以了解STAT1对CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的影响。
结果:
CTGF刺激人增生性瘢痕成纤维细胞后JAK-STATs通路所有蛋白(总蛋白以“t-”表示)均以非磷酸化和磷酸化(以“p-”表示)两种形式存在,在起始状态下即出现磷酸化条带,之后其磷酸化程度逐渐增强,在30min左右达峰值,再随时间延长逐渐下降呈一倒抛物线。Western blot显示胞浆及胞核中“p-JAK1/ t-JAK1”比值和“p-STAT1/ t-STAT1”比值随CTGF作用时间延长逐渐增大,至30min时达最强,之后逐渐下降。其余JAK-STATs蛋白虽均有不同程度的磷酸化,但并未随CTGF刺激出现反应性增强趋势。应用免疫荧光化学染色法检测STAT1的核转位,发现磷酸化STAT1蛋白在刺激30min左右达最强,比较组间差异发现:瘢痕成纤维细胞组(++):荧光明亮,胞浆、胞核分布基本一致;CTGF刺激瘢痕成纤维细胞组(+++-++++):荧光闪亮,呈明显的亮绿色,胞核中荧光强度增加,核聚集现象明显;应用凝胶阻滞电泳法,采用不同浓度CTGF刺激时发现检测STAT1与DNA的结合能力呈CTGF浓度依赖趋势,当CTGF 10ng/ml时达到峰值。同时,我们用10ng/ml CTGF刺激人增生性瘢痕成纤维细胞在不同时相点(0、10、20、30、45、60、90、120min)STAT1与DNA的结合能力及持续时间时发现:当CTGF刺激10min时,SIF已开始活化,45-60min达峰值,之后逐渐减弱,且较对照组明显增强。根据以上结果,初步筛选出JAK1、STAT1蛋白为参与CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的信号分子。
为进一步验证上述结论,我们将对象分为四组:①STAT1 ASODN+CTGF组;②CTGF刺激组;③STAT1 ASODN转染组;④空白对照组,观察STAT1对CTGF调控人增生性瘢痕成纤维细胞增殖分化过程的影响。在RT-PCR确定STAT1 ASODN已成功转入的前提下,用MTT测定转染前后细胞增殖程度变化时发现,增生性瘢痕成纤维细胞增殖程度呈②>④>①③的趋势变化,转染后细胞增殖明显受到抑制,结果具有统计学意义(P<0.05)。同时,我们采用RT-PCR比较转染前后a-SMA的差异,发现转染前后a-SMA/GAPDH条带灰度值无明显差异(P>0.05),结果不具有统计学意义。
结论:
1、在CTGF促进人增生性瘢痕成纤维细胞增殖与转分化的同时,JAK1和STAT1蛋白被不同程度活化,其活化程度随CTGF的刺激反应性增强,胞核中磷酸化STAT1荧光强度明显增加,核聚集现象明显;STAT1与DNA的结合能力增强。
2、STAT1 ASODN转染后人增生性瘢痕成纤维细胞增殖能力明显下降,但并未完全抑制其增殖过程;
3、STAT1 ASODN转染后人增生性瘢痕成纤维细胞向肌成纤维细胞的转分化能力则未见明显改变。
以上研究结果提示:STAT1参与了CTGF调控人增生性瘢痕成纤维细胞增殖过程,但并非是唯一途径;而JAK1则可能作为其上游因子,通过JAK1-STAT1通路参与了CTGF促进人增生性瘢痕成纤维细胞增殖过程。这从一定程度上揭示了CTGF调控人增生性瘢痕成纤维细胞增殖过程的信号转导机制,从而为抑制瘢痕纤维化提供了新的研究方向,有助于更深入地调控CTGF的促纤维化作用,为增生性瘢痕及其它纤维化疾病的研究及防治提供新的思路。
Hypertrophic scar is a quiz which needs to be solved in burn surgery.plastic surgery and all the trauma field.as the key effector cell,fibroblast is regulated by growth factor in the aspect of proliferation and differentiation.Connective tissue growth factor(CTGF) is a kind of fator which can promote fibrosis intensively and urge vitro-human hypertrophic scar fibroblast to differentiate to myofibroblast[1].But there is rare reports to its signal transduction mechanism.JAK-STATs pathway is a very important one which is found in recent years and play a part in cytokine signal transduction,and it paticipates in many physiological functions(eg. haematogenesis)and patho-functions(eg. Tumor.arthritis deformans.brain injured.bronchial asthma) [2-5].A lot of cytokines(eg. Interferon-α.β.γ, interleukin-2.4.6) .growth factors(eg. epidermal growth factor.platelet-derived growth factor) .growth hormone.leptin regulate proliferation and differentiation of many cells through JAK-STATs.Respecting the aboved reasons,we carry out the work to study the function of JAK-STATs pathway in proliferation and differentiation of human hypertrophic scar fibroblast induced by connective tissue growth factor.
Methods: cultivate hHSF with primary cultivation,then, divide the cells into two groups:①control group:hHSF②CTGF-stimulated group:hHSF with CTGF.The 1st part included:①Western-blot was used to detect proteins’activation including JAK1.JAK2.JAK3.TYK2.STAT1.STAT2.STAT3.STAT4.STAT5.STAT6 at 0min.5 min.10 min.20 min.30 min.45 min.60 min.90 min .②Immunofluorescence(IF)was used to verify nuclear translocation of the boltered protein.③Electrophoretic mobility shift assay(EMSA) was used to verify binding ability with DNA of the boltered protein.In the 2nd part,we divided cells into four groups:①STAT1 ASODN+CTGF group;②CTGF group;③STAT1 ASODN group;④control group.And then,we used MTT to detect the proliferation of hHSF and western-blot to detectα-SMA to learn the differentiation .
Results: In the premise that proliferation and differentiation of CTGF-stimulated group was much higher than that of control group(p<0.05),results of western-blot showed all the JAK-STATs proteins(“t-”) exists in two styles:non-phosphorylation and phosphorylation(“p-”).The phosphorylated protein appears at the beginnning,and then increased gradually,peaked at 30min,and fell-off afer 30mins.Among all the proteins ,only the ratio of“p-JAK1/ t-JAK1”and“p-STAT1/ t-STAT1”increased following CTGF stimulation. IF results showed phosphorylated STAT1 peaked at 30min.We compared the two groups and found:①control group(++):bright,flavo-green;②CTGF group(+++-++++): blink,obviouse bright green. EMSA told us that the binding ability of STAT1 and DNA depended on the concentration of CTGF,and peaked with the stimulation of 10ng/ml CTGF.And then,we used 10 ng/ml CTGF to stimulate hHSF at 0.10.20.30.45.60.90.120min and found that SIF was activated at 10min,peaked at 45-60min,fell-off gradully after 60min.The binding ability of CTGF group was much higher than that of control group.So JAK1.STAT1 was selected in preliminary screening.
And then ,we used STAT1 ASODN to block the STAT1.In the premise of sucessful transfection of STAT1 ASODN by RT-PCR,we found that the proliferation of hHSF was inhibited obviously with MTT afer ASODN transfection(P<0.05),but expression ofα-SMA changed little before and after the blockage of STAT1 ASODN(P>0.05). Conclusions:
1. At the same time of CTGF-stimulated proliferation and differentiation of hHSF,JAK1and STAT1was activated to some extent,and increased following CTGF stimulation.And fluorescence intensity of phosphorylated STAT1 and binding ability of STAT1and DNA increased obviously following the activation of CTGF;
2. The proliferation of hHSF was inhibited obviously but not all with MTT afer ASODN transfection(P<0.05);
3. Expression ofα-SMA changed little before and after the blockage of STAT1 ASODN(P>0.05).
STAT1 is important in the process of CTGF-induced proliferation of hHSF,but it’s not the only pathway to control the process.JAK1 may be the upstream element of STAT1 and may paticipate in the process of CTGF-induced proliferation of hHSF.The results above revealed the signal transduction mechanism of CTGF-induced proliferation of hHSF ,may afford new direction to inhibit scar fibrosis and contraction.
引文
1.李喆，李世荣，刘絉悖?结缔组织生长因子体外促进人增生性瘢痕成纤维细胞转分化的研究[J].第三军医大学学报,2006,28(8):775-777.
2.史克倩,林茂芳.JAK-STATs途径与正常造血及造血紊乱[J].医学综述,2002,8(4):225-227.
3.孙邵娟,王鸿程.JAK-STATs信号转导途径与肺癌的关系[J].国际呼吸杂志,2006,26(4):313-315.
4.翟秀珍,邹玉安.JAK-STATs信号通路与脑损伤[J].河北医科大学学报,2006,27(5):458-460.
5.周娟,符州.支气管哮喘与JAK/STAT信号转导途径[J].国外医学·生理.病理科学与临床分册,2004(4),24(2):197-9.
6. Ihn H. Pathogenesis of fibrosis: role of TGF-beta and CTGF[J]. Curr Opin Rheumatol, 2002, 14(6): 681-685.
7. Kothapalli D, Grotendorst GR . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts[J].J Cell Physiol,2000, 182(1):119.
8. Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene[J].Cell Growth Differ,1996,7(4):469.
9. Sakamoto H,Yasukawa H,Masuhara Ma , et al.Janus kinase inhibitor,JAB,is an interferon-gamma-inducible gene and confers resistance to interferons〔J〕.Blood,1998,92(5):1668-1676.
10.司徒镇强,吴军正主编.细胞培养.西安:世界图书出版公司,1996.
11. Zhang GS,Tu CQ,Zhang GY,et al. Indomethacin induces apoptosis and inhibits proliferation in chronic myeloid leukemia cells[J]. Leuk-Res,2000 May,24(5): 385-92.
12. Younai S,Nichter LS,Wellisz T,et al. Modulation of collagen synthesis by TGF beta in keloid and hypertrophic scar fibroblasts [J].Am Plast Surg,1994,33(1):148.
13.刘剑毅,李世荣,纪淑兴,等.病理性瘢痕中胶原纤维形态和结缔组织生长因子表达的检测[J].第三军医大学学报, 2003, 25(9): 818-821.
14.刘剑毅,李世荣,纪淑兴,等.病理性瘢痕中结缔组织生长因子基因的表达[J].中国修复重建外科杂志, 2003, (17)6: 436-438.
15.刘剑毅,李世荣,杨东运,等. HS不同时期结缔组织生长因子表达的动态研究[J].重庆医学, 2003, 32(5): 532-533.
16.刘剑毅,李世荣,纪淑兴,等.反义寡脱氧核苷酸对人K成纤维细胞CTGF基因表达和胶原合成的作用[J].中华烧伤杂志. 2004, 20(2): 72-75.。
17. Muchaneta-Kubara EC, Nahas AM. Myofibroblast phenotypes expression in experimental renal scarring [J]. NephrolDial Transplant, 1997,12:904.
18.程飚,付小兵,盛志勇,等.瘢痕组织中α-平滑肌肌动蛋白的表达与细胞凋亡的关系[J].中国病理生理杂志,2002,18(11):1333-6.
19. Oshea -J-J ,Notarangelo -L-D, Johnston -J-A,et al. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency [J]. J Clin Immunol, 1997, 17:431-447.
20.王关蒿,钱桂生,关菘,等. JAK-STATs信号转导及其临床意义[J].中国老年学杂志,2003,22:70-72.
21. Duronio V,Scheid M.P.,Ettinger S. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity [J].Cell Signalling,1998,10:233-239 .
22. Darnell–J-E, Kerr -I-M, Stark -G-R, et al. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins[J]. Science,1994, 264:1415-1419.
23. Kothapalli D, Grotendorst GR . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts[J].J Cell Physiol,2000, 182(1):119.
24. Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene[J].Cell Growth Differ,1996,7(4):469.
25. Frazier K, Wiliams S, Kothapalli D, et a1.Stimulation of fibroblast cell growth,matrix production,and granulation tissue formation by connective tissue growth factor[J].J Invest Dermatol,1996,107(3):404.
26. Kothapalli D, Grotendorst GR . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts[J].J Cell Physiol,2000, 182(1):119.
27. Shi-wen X, Pennington D, Holmes A, et a1.Autocrine overexpression of CTGFmaintains fibrosis:RDA analysis of fibrosis genes in systemic sclerosis[J].Exp Cell Res, 2000, 259(1):213.
28. Chen CC, Chen N, Lau LF.The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts[J].J BiolChem, 2001, 276(13):10443.
29. Shimo T, Nakanishi T, Kimura Y, et a1.Inhibition of endogenous expression of connective tsisue growth factor by its antisense oligonucleotide and antisense RNA suppreses proliferation and migration of vascular endothelial cells[J].J Biochem Tokyo, 1998, 124(1):130.
30. Babic AM, Chen CC, Lau LF.Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo[J].Mol Cell Biol, 1999, 19(4):2958.
31. Nakanishi T, Kimura Y, Tamura T, et a1.C1oning of a mRNA preferentially expressed in chondrocytes by differential display - PCR from a human chondroeytic cell line that is identical with connective tissue growth factor(CTGF)mRNA[J]. Biochem Biophys Res Commun, 1997, 234(1):206. 32. Xu J, Smock SL, Safadi FF, et a1.Cloning the full-length cDNA for rat connective tissue growth factor:impcations for skeletal development[J].J Cell Biochem, 2000, 77(1):103.
33.叶旭军,徐启勇,叶燕青,等.结缔组织生长因子在博莱霉素诱导大鼠肺纤维化模型中的表达及意义[J].中华结核和呼吸杂志, 2004, 27:407-409.
34. Paradis V, Dargere D, Vidaud M, et a1.Expression of connective tissue growth factor in experimental rat and human liver fibrosis[J].Hepatology, 1999, 30:968-976.
35. Hayashi N, Kakimuma T, Soma Y, et a1. Connective tissue growth factor is directly related to liver fibrosis [J] .Hepatogastroenterology, 2002, 49:133- 135.
36. Kurikawa N, Suga M, Kuroda S, et a1. An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells[J].Br J Pharmacol, 2003, 139: 1085- 1094.
37. Uchio K, Graham M, Dean NM, et al. Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis [J]. Wound Repair & Regeneration,2004, 12(1): 60-66.
38. Ito Y, Atco S, bootie RS, et a1.Expression of connective tissue growth factor in human renal fibrosis[J].Kidney Int, 1998, 53(4): 853-861.
39.赵青,陈楠,王伟铭,等.结缔组织生长因子在肾间质纤维化中的表达及其意义[J].肾脏病与透析肾移植杂志, 2002, 11(1): 21-6.
40. Hideki Yokoi, Masashi Mukoyama, Tetsuya Nagae, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis [J]. Journal of the American Society of Nephrology, 2004, 15(6):1430-1440.
41. Ohnishi H, Oka T, Kusachi S, et al. Increased expression of connective tissue growth factor in the infarct zone of experimentally induced myocardial infarction in rats[J].J. Mol Cell Cardial, 1998, 30(11):2411-2422.
42. Chen MM, Lan AA, Abraham SA, et al. CTGF expression is induced by TGF-βin cardiac fibroblasts and cardiac myocytes:a potential role in heart fibrosis[J]. J Mol Cell Cardial, 2000, 32:1805-1819.
43. lgarashi A, Nashiro K, Kikuchi K, et a1.Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis[J].J Invest Dermatol, 1995, 105:280-284.
44. Igarashi A, Nashiro K, Kikuchi K. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders[J].J Invest Dermatol, 1996, 106:729-733.
45. Sato S, Nagaoka T, Hasegawa M, et a1. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis:association with extent of skin sclerosis and severity of pulmonary fibrosis[J].J Rheumatol, 2000, 27:149-154.
46. Cook PD. Medicinal chemistry of antisense oligonucleotides—future opportunities[J]. Anticancer Drug Des, 1991, 6(6):585-607.
47. hao Q, Matson S, Herrera CJ, et al. Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate, and mixed phosphorothioate andmethylphosphonate oligonucleotides[J]. Antisense Res Dev, 1993, 3(1):53-66.
48.成党校,黄桂君,钱桂生.新型基因转染阳离子脂质体研究进展[J].国外医学药学分册,2000,27(5):257-260.
49. F.奥斯伯,R.E金斯顿,J.G.塞得曼等著.颜子颖,王海林译.精编分子生物学实验指南.第一版.北京:科学出版社,2001:274-277.
50.蔡文琴,王泊沄主编.实用免疫细胞化学与核酸分子杂交技术.第一版.成都:四川科学技术出版社,1994:55.
51.张树民.JAK-STATs和免疫系统的关系[J].国外医学免疫学分册, 1999 ,22(5):294-297.
52. Fujitani YM,Hibi,-M, Fukada,-T,et al. An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT[J] . Oncogene,1997,14:751-761.
53. Bhattacharya -S,Eckner -R,Grossman -S,et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha[J]. Nature,1996,383(6598): 344-7.
1. Bolli R,Dawn B,Xuan YT.Role of the jak/stat pathway in protection against.myocardial ischemia/reperfusion injury [J].Trends Cardiovasc Med,2003,13(2):72-79.
2. Guo Y,Mascarenono E,Siddiqui MAQ.The role of JAK/STAT pathway in the regulation of ANG gene expression[J].Am J Hypertens,2002,15(Supplement10):214.
3. Liang S,Wei H,Sun R,et al.IFN-a regulates Nkcell cytotoxicity through STAT1 pathway[J].Cytokine,2003,2(6):190-199.
4. Oshea -J-J ,Notarangelo -L-D, Johnston -J-A,et al. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency [J]. J Clin Immunol, 1997, 17:431-447.
5.王关蒿,钱桂生,关菘等.JAK-STATs信号转导及其临床意义.中国老年学杂志,2003,22:70-72.
6. Duronio V,Scheid M.P.,Ettinger S. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity [J].Cell Signalling,1998,10:233-239 .
7. Darnell–J-E, Kerr -I-M, Stark -G-R, et al. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins[J]. Science,1994, 264:1415-1419.
8. Verbsky J W,Bach E A,Fang Y F,et al.Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cell[J]. J Biol Chem,1996,271(24):13976-80.
9.张树民.JAK-STATs和免疫系统的关系[J].国外医学免疫学分册.1999,22(5):294-297
10.谵登兵,张日,夏学鸣.GM-CSF诱导TF-1白血病细胞JAK-STATs表达研究[J].江苏医药杂志,2003,29(4):305-6
11. Cacalano NA,Migone TS,Bazan F,et al.Autosomal SCID causedby a point mutation in the of JAK smapping of the Jak3-receptor interaction domain[J]. EMBOJ,1999, 18(5):1549-1558.
12. Aracasoy MO,Harris KW,Forget BG.A human erythropoietin receptor gene mutant causing famillal erythrocytosis is associated with dergulation of the rates of Jak2 and Stat5 in activation[J].Exp Hematol,1999,27(1):63-74.
13. Johnston JA,Kawamura M,Kirken RA,et al.Phosphorylation and activation of the Jaks kinase in response to inerleukin-2[J].Nature,1994,370(2):151-153.
14.史克倩,林茂芳.JAK-STATs途径与正常造血及造血紊乱[J].医学综述,2002,8(4):225-227.
15. Hoefsloot LH,vanAnelsvoort MP,Broeders LCAM,et al.Erythropoietion induced activation of STAT5 is impaired in the myelodyplastic syndrome[J]. Blood,1997, 89(45):1690-1700.
16. Sakanoto H,Yasukawa H,Masuhara M,et al.A Janus kinase inhibitor JAB is an interferon-γinducible gene and confers resistance to interferons[J]. Blood,1998, 92(4):1668-1676.
17. Rathun RK,Faulkner GR,Ostroki MH,et al.Inactivation of the Fancoin anemia group C gene angments interferon-gamma-induced apoptotic response in hemalopoietic cells[J].Blood,1997,90(2):974-983.
18. Pamg Q,Fagerlie S,Christianson TA,et al.TheFanconi anemia(FC) protein FAC is required for recruitoment of Stat1 to the IFN-γreceptor complex[abstract] [J].Blood, 1998,92(3):476.
19. Aracasoy MO,Harris KW,Forget BG.A human erythropoietin receptor gene mutant causing famillal erythrocytosis is associated with dergulation of the rates of Jak2 and Stat5 in activation[J].Exp Hematol,1999,27(1):63-74.
20.孙邵娟,王鸿程. JAK-STATs信号转导途径与肺癌的关系[J].国际呼吸杂志,2006,26(4):313-315.
21.曹贵方,杨期东. JAK-STATs信号转导途径与脑缺血[J].国外医学神经病学神经外科学分册.2004,31(4):340-343.
22. Takagi Y,Harada J,Chiarugi A,et al.STAT1 is activated in neurons after ischemia and contributes to ischemic brain injury[J].J Cereb Blood Flow Metab,2002, 22(11): 1311-1318.
23. Justicia C,Gabriel C,Planas AM.Activation of the JAK/STAT pathway following transient focal cerebral ischmia: signaling through Jak1 and Stat3 in astrocytes[J]. Glia,2000,30(2):253-270.
24. Suzuki S,Tanaka K,Nogawa S,et al.Phosphoryrlation of signal transducer and activator of transcription 3(stat3) after focal cerebral ischemia in rats[J].Exp Neurol, 2001,170(1):63-71.
25.周娟,符州.支气管哮喘与JAK/STAT信号转导途径[J].国外医学·生理.病理科学与临床分册.2004(4),24(2):197-9.
26.翟秀珍,邹玉安.JAK-STATs信号通路与脑损伤[J].河北医科大学学报.2006,27(5):458-460.
27. Song M.M.,Shuai K.The uppressor of cytokine signaling SOCS 1 and S0CS3 but not SOCS2 proteins inhibit interferon-mediated anti-viral and anti-proliferative activities[J].J Biol Chem,1998,273:35056.
28.李积东,吴洪福,耿排力.JAK-STATs信号转导通路的负调节机制[J].青海医学院学报.2005,26(2):134-136.
29.张树民,洪梅.JAK-STATs信号转导机制及其与Ras通路的关系[J].国外医学分子生物学分册.1999,21(4):218-222.
30. Bhattacharya -S,Eckner -R,Grossman -S,et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha[J]. Nature,1996,383(6598): 344-7.
31. Watanabe S,Itoh T,Arai K.Roles of STAT Kinase in human GM-CSF receptor signals[J].Leukemia,1997,11[Suppl3]:76-78.
32. Shimoda K,Feng J,Murakaim H,et al.STAT1 plays an essential role for resptor phosphorylation and Statactivation in response to granulocyte colony-stimulating factor[J].Blood,1997,90(2):597-604.
33. Fujitani Y,Hibi M,Fukada T,et al.An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT[J]. Oncogene,1997,14(7):751-761
2.史克倩,林茂芳.JAK-STATs途径与正常造血及造血紊乱[J].医学综述,2002,8(4):225-227.
3.孙邵娟,王鸿程.JAK-STATs信号转导途径与肺癌的关系[J].国际呼吸杂志,2006,26(4):313-315.
4.翟秀珍,邹玉安.JAK-STATs信号通路与脑损伤[J].河北医科大学学报,2006,27(5):458-460.
5.周娟,符州.支气管哮喘与JAK/STAT信号转导途径[J].国外医学·生理.病理科学与临床分册,2004(4),24(2):197-9.
6. Ihn H. Pathogenesis of fibrosis: role of TGF-beta and CTGF[J]. Curr Opin Rheumatol, 2002, 14(6): 681-685.
7. Kothapalli D, Grotendorst GR . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts[J].J Cell Physiol,2000, 182(1):119.
8. Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene[J].Cell Growth Differ,1996,7(4):469.
9. Sakamoto H,Yasukawa H,Masuhara Ma , et al.Janus kinase inhibitor,JAB,is an interferon-gamma-inducible gene and confers resistance to interferons〔J〕.Blood,1998,92(5):1668-1676.
10.司徒镇强,吴军正主编.细胞培养.西安:世界图书出版公司,1996.
11. Zhang GS,Tu CQ,Zhang GY,et al. Indomethacin induces apoptosis and inhibits proliferation in chronic myeloid leukemia cells[J]. Leuk-Res,2000 May,24(5): 385-92.
12. Younai S,Nichter LS,Wellisz T,et al. Modulation of collagen synthesis by TGF beta in keloid and hypertrophic scar fibroblasts [J].Am Plast Surg,1994,33(1):148.
13.刘剑毅,李世荣,纪淑兴,等.病理性瘢痕中胶原纤维形态和结缔组织生长因子表达的检测[J].第三军医大学学报, 2003, 25(9): 818-821.
14.刘剑毅,李世荣,纪淑兴,等.病理性瘢痕中结缔组织生长因子基因的表达[J].中国修复重建外科杂志, 2003, (17)6: 436-438.
15.刘剑毅,李世荣,杨东运,等. HS不同时期结缔组织生长因子表达的动态研究[J].重庆医学, 2003, 32(5): 532-533.
16.刘剑毅,李世荣,纪淑兴,等.反义寡脱氧核苷酸对人K成纤维细胞CTGF基因表达和胶原合成的作用[J].中华烧伤杂志. 2004, 20(2): 72-75.。
17. Muchaneta-Kubara EC, Nahas AM. Myofibroblast phenotypes expression in experimental renal scarring [J]. NephrolDial Transplant, 1997,12:904.
18.程飚,付小兵,盛志勇,等.瘢痕组织中α-平滑肌肌动蛋白的表达与细胞凋亡的关系[J].中国病理生理杂志,2002,18(11):1333-6.
19. Oshea -J-J ,Notarangelo -L-D, Johnston -J-A,et al. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency [J]. J Clin Immunol, 1997, 17:431-447.
20.王关蒿,钱桂生,关菘,等. JAK-STATs信号转导及其临床意义[J].中国老年学杂志,2003,22:70-72.
21. Duronio V,Scheid M.P.,Ettinger S. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity [J].Cell Signalling,1998,10:233-239 .
22. Darnell–J-E, Kerr -I-M, Stark -G-R, et al. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins[J]. Science,1994, 264:1415-1419.
23. Kothapalli D, Grotendorst GR . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts[J].J Cell Physiol,2000, 182(1):119.
24. Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene[J].Cell Growth Differ,1996,7(4):469.
25. Frazier K, Wiliams S, Kothapalli D, et a1.Stimulation of fibroblast cell growth,matrix production,and granulation tissue formation by connective tissue growth factor[J].J Invest Dermatol,1996,107(3):404.
26. Kothapalli D, Grotendorst GR . CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts[J].J Cell Physiol,2000, 182(1):119.
27. Shi-wen X, Pennington D, Holmes A, et a1.Autocrine overexpression of CTGFmaintains fibrosis:RDA analysis of fibrosis genes in systemic sclerosis[J].Exp Cell Res, 2000, 259(1):213.
28. Chen CC, Chen N, Lau LF.The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts[J].J BiolChem, 2001, 276(13):10443.
29. Shimo T, Nakanishi T, Kimura Y, et a1.Inhibition of endogenous expression of connective tsisue growth factor by its antisense oligonucleotide and antisense RNA suppreses proliferation and migration of vascular endothelial cells[J].J Biochem Tokyo, 1998, 124(1):130.
30. Babic AM, Chen CC, Lau LF.Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo[J].Mol Cell Biol, 1999, 19(4):2958.
31. Nakanishi T, Kimura Y, Tamura T, et a1.C1oning of a mRNA preferentially expressed in chondrocytes by differential display - PCR from a human chondroeytic cell line that is identical with connective tissue growth factor(CTGF)mRNA[J]. Biochem Biophys Res Commun, 1997, 234(1):206. 32. Xu J, Smock SL, Safadi FF, et a1.Cloning the full-length cDNA for rat connective tissue growth factor:impcations for skeletal development[J].J Cell Biochem, 2000, 77(1):103.
33.叶旭军,徐启勇,叶燕青,等.结缔组织生长因子在博莱霉素诱导大鼠肺纤维化模型中的表达及意义[J].中华结核和呼吸杂志, 2004, 27:407-409.
34. Paradis V, Dargere D, Vidaud M, et a1.Expression of connective tissue growth factor in experimental rat and human liver fibrosis[J].Hepatology, 1999, 30:968-976.
35. Hayashi N, Kakimuma T, Soma Y, et a1. Connective tissue growth factor is directly related to liver fibrosis [J] .Hepatogastroenterology, 2002, 49:133- 135.
36. Kurikawa N, Suga M, Kuroda S, et a1. An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells[J].Br J Pharmacol, 2003, 139: 1085- 1094.
37. Uchio K, Graham M, Dean NM, et al. Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis [J]. Wound Repair & Regeneration,2004, 12(1): 60-66.
38. Ito Y, Atco S, bootie RS, et a1.Expression of connective tissue growth factor in human renal fibrosis[J].Kidney Int, 1998, 53(4): 853-861.
39.赵青,陈楠,王伟铭,等.结缔组织生长因子在肾间质纤维化中的表达及其意义[J].肾脏病与透析肾移植杂志, 2002, 11(1): 21-6.
40. Hideki Yokoi, Masashi Mukoyama, Tetsuya Nagae, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis [J]. Journal of the American Society of Nephrology, 2004, 15(6):1430-1440.
41. Ohnishi H, Oka T, Kusachi S, et al. Increased expression of connective tissue growth factor in the infarct zone of experimentally induced myocardial infarction in rats[J].J. Mol Cell Cardial, 1998, 30(11):2411-2422.
42. Chen MM, Lan AA, Abraham SA, et al. CTGF expression is induced by TGF-βin cardiac fibroblasts and cardiac myocytes:a potential role in heart fibrosis[J]. J Mol Cell Cardial, 2000, 32:1805-1819.
43. lgarashi A, Nashiro K, Kikuchi K, et a1.Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis[J].J Invest Dermatol, 1995, 105:280-284.
44. Igarashi A, Nashiro K, Kikuchi K. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders[J].J Invest Dermatol, 1996, 106:729-733.
45. Sato S, Nagaoka T, Hasegawa M, et a1. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis:association with extent of skin sclerosis and severity of pulmonary fibrosis[J].J Rheumatol, 2000, 27:149-154.
46. Cook PD. Medicinal chemistry of antisense oligonucleotides—future opportunities[J]. Anticancer Drug Des, 1991, 6(6):585-607.
47. hao Q, Matson S, Herrera CJ, et al. Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate, and mixed phosphorothioate andmethylphosphonate oligonucleotides[J]. Antisense Res Dev, 1993, 3(1):53-66.
48.成党校,黄桂君,钱桂生.新型基因转染阳离子脂质体研究进展[J].国外医学药学分册,2000,27(5):257-260.
49. F.奥斯伯,R.E金斯顿,J.G.塞得曼等著.颜子颖,王海林译.精编分子生物学实验指南.第一版.北京:科学出版社,2001:274-277.
50.蔡文琴,王泊沄主编.实用免疫细胞化学与核酸分子杂交技术.第一版.成都:四川科学技术出版社,1994:55.
51.张树民.JAK-STATs和免疫系统的关系[J].国外医学免疫学分册, 1999 ,22(5):294-297.
52. Fujitani YM,Hibi,-M, Fukada,-T,et al. An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT[J] . Oncogene,1997,14:751-761.
53. Bhattacharya -S,Eckner -R,Grossman -S,et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha[J]. Nature,1996,383(6598): 344-7.
1. Bolli R,Dawn B,Xuan YT.Role of the jak/stat pathway in protection against.myocardial ischemia/reperfusion injury [J].Trends Cardiovasc Med,2003,13(2):72-79.
2. Guo Y,Mascarenono E,Siddiqui MAQ.The role of JAK/STAT pathway in the regulation of ANG gene expression[J].Am J Hypertens,2002,15(Supplement10):214.
3. Liang S,Wei H,Sun R,et al.IFN-a regulates Nkcell cytotoxicity through STAT1 pathway[J].Cytokine,2003,2(6):190-199.
4. Oshea -J-J ,Notarangelo -L-D, Johnston -J-A,et al. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency [J]. J Clin Immunol, 1997, 17:431-447.
5.王关蒿,钱桂生,关菘等.JAK-STATs信号转导及其临床意义.中国老年学杂志,2003,22:70-72.
6. Duronio V,Scheid M.P.,Ettinger S. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity [J].Cell Signalling,1998,10:233-239 .
7. Darnell–J-E, Kerr -I-M, Stark -G-R, et al. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins[J]. Science,1994, 264:1415-1419.
8. Verbsky J W,Bach E A,Fang Y F,et al.Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cell[J]. J Biol Chem,1996,271(24):13976-80.
9.张树民.JAK-STATs和免疫系统的关系[J].国外医学免疫学分册.1999,22(5):294-297
10.谵登兵,张日,夏学鸣.GM-CSF诱导TF-1白血病细胞JAK-STATs表达研究[J].江苏医药杂志,2003,29(4):305-6
11. Cacalano NA,Migone TS,Bazan F,et al.Autosomal SCID causedby a point mutation in the of JAK smapping of the Jak3-receptor interaction domain[J]. EMBOJ,1999, 18(5):1549-1558.
12. Aracasoy MO,Harris KW,Forget BG.A human erythropoietin receptor gene mutant causing famillal erythrocytosis is associated with dergulation of the rates of Jak2 and Stat5 in activation[J].Exp Hematol,1999,27(1):63-74.
13. Johnston JA,Kawamura M,Kirken RA,et al.Phosphorylation and activation of the Jaks kinase in response to inerleukin-2[J].Nature,1994,370(2):151-153.
14.史克倩,林茂芳.JAK-STATs途径与正常造血及造血紊乱[J].医学综述,2002,8(4):225-227.
15. Hoefsloot LH,vanAnelsvoort MP,Broeders LCAM,et al.Erythropoietion induced activation of STAT5 is impaired in the myelodyplastic syndrome[J]. Blood,1997, 89(45):1690-1700.
16. Sakanoto H,Yasukawa H,Masuhara M,et al.A Janus kinase inhibitor JAB is an interferon-γinducible gene and confers resistance to interferons[J]. Blood,1998, 92(4):1668-1676.
17. Rathun RK,Faulkner GR,Ostroki MH,et al.Inactivation of the Fancoin anemia group C gene angments interferon-gamma-induced apoptotic response in hemalopoietic cells[J].Blood,1997,90(2):974-983.
18. Pamg Q,Fagerlie S,Christianson TA,et al.TheFanconi anemia(FC) protein FAC is required for recruitoment of Stat1 to the IFN-γreceptor complex[abstract] [J].Blood, 1998,92(3):476.
19. Aracasoy MO,Harris KW,Forget BG.A human erythropoietin receptor gene mutant causing famillal erythrocytosis is associated with dergulation of the rates of Jak2 and Stat5 in activation[J].Exp Hematol,1999,27(1):63-74.
20.孙邵娟,王鸿程. JAK-STATs信号转导途径与肺癌的关系[J].国际呼吸杂志,2006,26(4):313-315.
21.曹贵方,杨期东. JAK-STATs信号转导途径与脑缺血[J].国外医学神经病学神经外科学分册.2004,31(4):340-343.
22. Takagi Y,Harada J,Chiarugi A,et al.STAT1 is activated in neurons after ischemia and contributes to ischemic brain injury[J].J Cereb Blood Flow Metab,2002, 22(11): 1311-1318.
23. Justicia C,Gabriel C,Planas AM.Activation of the JAK/STAT pathway following transient focal cerebral ischmia: signaling through Jak1 and Stat3 in astrocytes[J]. Glia,2000,30(2):253-270.
24. Suzuki S,Tanaka K,Nogawa S,et al.Phosphoryrlation of signal transducer and activator of transcription 3(stat3) after focal cerebral ischemia in rats[J].Exp Neurol, 2001,170(1):63-71.
25.周娟,符州.支气管哮喘与JAK/STAT信号转导途径[J].国外医学·生理.病理科学与临床分册.2004(4),24(2):197-9.
26.翟秀珍,邹玉安.JAK-STATs信号通路与脑损伤[J].河北医科大学学报.2006,27(5):458-460.
27. Song M.M.,Shuai K.The uppressor of cytokine signaling SOCS 1 and S0CS3 but not SOCS2 proteins inhibit interferon-mediated anti-viral and anti-proliferative activities[J].J Biol Chem,1998,273:35056.
28.李积东,吴洪福,耿排力.JAK-STATs信号转导通路的负调节机制[J].青海医学院学报.2005,26(2):134-136.
29.张树民,洪梅.JAK-STATs信号转导机制及其与Ras通路的关系[J].国外医学分子生物学分册.1999,21(4):218-222.
30. Bhattacharya -S,Eckner -R,Grossman -S,et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha[J]. Nature,1996,383(6598): 344-7.
31. Watanabe S,Itoh T,Arai K.Roles of STAT Kinase in human GM-CSF receptor signals[J].Leukemia,1997,11[Suppl3]:76-78.
32. Shimoda K,Feng J,Murakaim H,et al.STAT1 plays an essential role for resptor phosphorylation and Statactivation in response to granulocyte colony-stimulating factor[J].Blood,1997,90(2):597-604.
33. Fujitani Y,Hibi M,Fukada T,et al.An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT[J]. Oncogene,1997,14(7):751-761