p27~（kip1）磷酸化异常与非霍奇金淋巴瘤相关性研究
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摘要
目的
1.分别研究p27~(kip1) 2个主要磷酸化位点—187位苏氨酸(Thr)和10位丝氨酸(Ser),在非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)病例中的异常磷酸化情况,结合增殖指标Ki-67、p27~(kip1)相关蛋白Skp2、Jab1及临床相关资料,初步探讨p27~(kip1)异常磷酸化与NHL发生、发展的关系。
2.在细胞水平,分别探讨p27~(kip1)Thr187、Ser10磷酸化异常与淋巴瘤细胞生长周期的关系。
方法
1.首先在组织水平,选取116例NHL,其中惰性NHL18例,包括11例滤泡性淋巴瘤(Follicular center cell lymphoma)和7例胃肠黏膜相关淋巴组织淋巴瘤(Marginal zone B-cell lymphoma of MALT type);侵袭性NHL98例,包括37例弥漫性大B细胞淋巴瘤(Diffuse large B-cell lymphoma),49例鼻NK/T细胞淋巴瘤(NK/T lymphoma),12例外周非特殊型T细胞淋巴瘤(Unspecified peripheral T-cell lymphoma)。另取同时期保存的15例良性增生淋巴结作为对照。采用免疫组化方法,检测Thr187磷酸化p27~(kip1)、Ser10磷酸化p27~(kip1)及p27~(kip1)相关分子Jab1表达情况,SPSS13.0统计软件分析数据。
2.采用RT-PCR技术扩增人类Jab1全长序列,通过DNA重组技术分别将其重组于pcDNA3.1-Myc及pcDNA3.1载体,构建Jab1正义表达质粒,酶切电泳分析及DNA测序的方法对重组表达质粒进行鉴定。
3.采用血清饥饿合并释放同步化处理淋巴瘤细胞,流式细胞仪检测细胞周期,Western blot、免疫荧光、免疫沉淀及核浆分离技术检测Thr187磷酸化p27~(kip1)、Ser10磷酸化p27~(kip1)及p27~(kip1)相关分子Skp2、Jab1等在细胞内的表达、亚细胞定位。应用pcDNA3.1-Myc-Jab1表达质粒采用脂质体瞬时转染淋巴瘤细胞,流式细胞仪分析增加Jab1表达对淋巴瘤细胞周期的影响,Western blot、免疫荧光、核浆分离及免疫沉淀检测Jab1过表达对p27~(kip1)的表达、亚细胞定位及功能的影响。
结果
1.免疫组化结果显示:1) NHL中Thr187磷酸化p27~(kip1)阳性率明显高于良性增生性淋巴结中(生发中心以外)的表达水平。结合临床资料分析显示:Thr187磷酸化p27~(kip1)与NHL病人的年龄、临床分期有相关性。病人年龄越大,临床分期越晚,其阳性率越高;与NHL病人性别、淋巴结转移情况无明显相关性。相关分析显示:Thr187磷酸化p27~(kip1)与Ki-67表达呈正相关(rs = 0.639,P<0.001);Thr187磷酸化p27~(kip1)与Skp2表达呈正相关(rs= 0.594,P<0.001);Thr187磷酸化p27~(kip1)与p27~(kip1)的表达呈正相关(rs = 0.175,P<0.001)。生存分析显示:Thr187p27~(kip1)磷酸化阳性(>10%)的病人,其五年生存率明显低于阴性(≤10%)的病人(P < 0.001)。2) Ser10磷酸化p27~(kip1)、Jab1蛋白阳性率均明显高于良性增生性淋巴结中(生发中心以外)的表达水平。结合临床资料分析显示:Ser10磷酸化p27~(kip1)、Jab1蛋白表达与NHL临床分期有相关性。与NHL病人年龄、性别、淋巴结转移情况无明显相关性。相关分析显示:Ser10磷酸化p27~(kip1)与Ki-67表达无明显相关性;Ser10磷酸化p27~(kip1)与Jab1表达呈正相关(rs= 0.696,P<0.001);Ser10磷酸化p27~(kip1)与p27~(kip1)的表达呈负相关(rs = -0.457,P<0.001);Jab1蛋白与增殖指标Ki-67表达呈正相关(rs = 0.870,P<0.001);Jab1蛋白与p27~(kip1)蛋白表达呈明显负相关(rs = -0.380,P<0.001)。生存分析显示:Ser10磷酸化p27~(kip1)阳性(>10%)、Jab1阳性(>10%)的病人,其五年生存率均明显低于阴性(≤10%)的病人(P < 0.001)。
2.构建pcDNA3.1-Myc-Jab1正义表达质粒,通过酶切电泳分析及DNA测序的方法对重组表达质粒进行鉴定,证实构建成功。
3.血清饥饿合并释放能够刺激淋巴瘤细胞同步化生长,随着细胞周期进程:1)Thr187磷酸化p27~(kip1)表达增加,并且主要位于胞核内;p27~(kip1)对cyclinE/CDK2复合物抑制作用减弱,CDK2激酶活性增强。2)Ser10磷酸化p27~(kip1)与Jab1表达明显增加;Jab1过表达导致p27~(kip1)磷酸化形式改变,胞浆分布增多,与CDK分子的亲和能力改变,最终促进细胞进入S期。
结论
1. p27~(kip1)Thr187、Ser10两个位点的磷酸化异常与NHL病例恶性程度密切相关。提示:p27~(kip1)Thr187、Ser10两个磷酸化位点可能分别通过不同途径使p27~(kip1)表达及功能发生异常,导致细胞周期失控并促进细胞异常增殖,从而参与了NHL的发生和发展。
2.成功构建了人类Jab1正义表达质粒,为进一步探讨Jab1基因在NHL发生发展中的作用奠定了实验基础。
3.在细胞水平,Thr187磷酸化p27~(kip1)可能通过泛素-蛋白酶体途径影响p27~(kip1)的降解,而Ser10磷酸化p27~(kip1)与Jab1从介导p27~(kip1)出核这一途径影响p27~(kip1)的核内外分布,两个磷酸化位点通过各自的功能特点调节p27~(kip1)的表达及功能,从而参与对淋巴瘤细胞生长的调控。
Objectives
1. To investigate the expressions of 2 major phosphorylation formats of p27~(kip1) respectively and its relative protein S-phase kinase-associated protein 2(Skp2) and Jun activation domain binding protein 1 (Jab1) in human non-Hodgkin’s Lymphomas and their clinicopathologic significance.
2. To evaluate the specific effects of pThr187p27~(kip1) and pSer10p27~(kip1) during lymphoma cell growth.
Methods
1. Immunohistochemical technique was used to detect the expression levels of pThr187p27~(kip1), pSer10p27~(kip1)p27~(kip1), Skp2, Jab1 and Ki-67 in 116 cases of NHLs and 15 cases of reactive lymphoid tissue. The NHL cases characterized in this study were universal in oriental included: 11 follicular lymphomas (FL), 7 mucosa-associated lymphoid tissue B cell lymphomas (MALT), 37 diffuse large B-cell lymphomas (DLBCL), 49 Nasal natural killer (NK)/T-cell lymphomas and 12 unspecified peripheral T-cell lymphomas (PT-un).
2. Human Jab1 complete cDNA was amplified by RT-PCR method, and was reconstructed into the eukaryotic expressive vector pcDNA3.1-Myc to form the Jab1 sense expressive plasmid. The reconstructed DNA was identified by enzyme digestion and DNA sequencing.
3. Serum starvation and release used to synchronize lymphoma cells. Flow cytometer was used to analyze cell-cycles. The expression and subcellular localization of pThr187p27~(kip1), pSer10p27~(kip1), Skp2 and Jab1 were detected by western blot, immunoflurescence and subcellular fractionation. Transfection was performed using lipofectamine 2000 transfection reagent according to the manufacture’s protocol. The cells were harvested 48 h after transfection and cell-cycles were detected by Flow cytometry. The expression and subcellular localization of Jab1, p27~(kip1) and p-Ser10p27~(kip1) were investigated by western blot, immunoflurescence, immunoprecipitation and subcellular fractionation.
Results
1. Immunohistochemistry analysis showed: 1) The expression level of pThr187p27~(kip1) in NHLs was higher than that in reactive lymphoid tissues (except germinal center). Using a 10% cutoff for pThr187p27~(kip1) expression, pThr187p27~(kip1) positive expression was significantly associated with patients’age and clinical stage, but it was not associated with patients’sex and lymph node metastasis. In all cases of NHLs analyzed, pThr187p27~(kip1) expression did correlate with expression of Skp2 (rs =0.594, P<0.001) and p27~(kip1) (rs =0.175, P=0.062) as well as Ki-67 (rs =0.639, P<0.001). By using the Kaplan-Meier analysis, patients with pThr187p27~(kip1)-positive tumor were significantly associated with short overall survival (P < 0.001). 2) The expression levels of pSer10p27~(kip1) and Jab1 in NHLs were higher than that in reactive lymphoid tissues (except germinal center). Using a 10% for cutoff, pSer10p27~(kip1) and Jab1 overexpression were both significantly associated with advanced stage, but they were not associated with patients’age, sex and lymph node metastasis. As continuous variables, pSer10p27~(kip1) expression did positively correlated with expression of Jab1(rs= 0.696, P<0.001) and negatively correlated with expression of p27~(kip1) (rs = -0.457,P<0.001); Jab1 expression was negatively associated with p27~(kip1) expression (rs = -0.380, P <0.001) and was positively associated with Ki-67 expression (rs = 0.870, P < 0.001) in all cases of NHLs analyzed. Survival analysis indicated that patients with pSer10p27~(kip1) or Jab1-positive tumor were significantly associated with short overall survival (P < 0.001).
2. The cloned DNA was confirmed to be human Jab1 cDNA.
3. Advances in the cell cycle study have revealed: 1) pThr187p27~(kip1) increased as the cells were treated with serum addition as well as the same kinetics were observed at cyclin E and CDK2. Subcellular fractionation showed that pThr187p27~(kip1) was mainly present in the nucleus of cells released from G1, leading to the dramatically reduced p27~(kip1) accumulation. Immunoprecipitation studies suggested that the enhancement of phosphorylation at Thr187 of p27~(kip1) mainly occurred in the CDK2/CyclinE complex. 2) pSer10p27~(kip1) and Jab1 were also cell-cycle dependent, being present in proliferating cells but undetectable in G1 cells. We’ve found that overexpression of Jab1 could increasing the Ser10 and Thr157 phosphorylation of p27~(kip1) while the Thr187 phosphorylation was significantly decreased. Our preliminary data demonstrated a significant decrease of p27~(kip1) expression level and a significant increase of S phase of the cell cycle in NHL cell lines that overexpressed Jab1. Immunoprecipitation studies suggested that Jab1 could change in p27~(kip1) binding preferences to CDKs and relatively major p27~(kip1)preferentially bound to CDK4.
Conclusions
1. Increased expression levels of pThr187p27~(kip1) and pSer10-p27~(kip1) were closely correlated with the aggressiveness of NHLs. Both 2 major phosphrylation formats may influence the expression and function of p27~(kip1) through different pathways, thus may play key roles in the occurrence and development of NHLs.
2. We successfully cloned human Jab1 gene and constructed its eukaryotic expressive plasmid, which was an ideal model for further study.
3. Since Thr187 phosphorylation is required for p27~(kip1) ubiquitination and Ser10 phosphorylation is necessary for the nuclear export of the protein mediated by the exportin Jab1, both phosphorylation formats may be involved in the control of the G1-S transition and have oncogenic potential.
1.分别研究p27~(kip1) 2个主要磷酸化位点—187位苏氨酸(Thr)和10位丝氨酸(Ser),在非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)病例中的异常磷酸化情况,结合增殖指标Ki-67、p27~(kip1)相关蛋白Skp2、Jab1及临床相关资料,初步探讨p27~(kip1)异常磷酸化与NHL发生、发展的关系。
2.在细胞水平,分别探讨p27~(kip1)Thr187、Ser10磷酸化异常与淋巴瘤细胞生长周期的关系。
方法
1.首先在组织水平,选取116例NHL,其中惰性NHL18例,包括11例滤泡性淋巴瘤(Follicular center cell lymphoma)和7例胃肠黏膜相关淋巴组织淋巴瘤(Marginal zone B-cell lymphoma of MALT type);侵袭性NHL98例,包括37例弥漫性大B细胞淋巴瘤(Diffuse large B-cell lymphoma),49例鼻NK/T细胞淋巴瘤(NK/T lymphoma),12例外周非特殊型T细胞淋巴瘤(Unspecified peripheral T-cell lymphoma)。另取同时期保存的15例良性增生淋巴结作为对照。采用免疫组化方法,检测Thr187磷酸化p27~(kip1)、Ser10磷酸化p27~(kip1)及p27~(kip1)相关分子Jab1表达情况,SPSS13.0统计软件分析数据。
2.采用RT-PCR技术扩增人类Jab1全长序列,通过DNA重组技术分别将其重组于pcDNA3.1-Myc及pcDNA3.1载体,构建Jab1正义表达质粒,酶切电泳分析及DNA测序的方法对重组表达质粒进行鉴定。
3.采用血清饥饿合并释放同步化处理淋巴瘤细胞,流式细胞仪检测细胞周期,Western blot、免疫荧光、免疫沉淀及核浆分离技术检测Thr187磷酸化p27~(kip1)、Ser10磷酸化p27~(kip1)及p27~(kip1)相关分子Skp2、Jab1等在细胞内的表达、亚细胞定位。应用pcDNA3.1-Myc-Jab1表达质粒采用脂质体瞬时转染淋巴瘤细胞,流式细胞仪分析增加Jab1表达对淋巴瘤细胞周期的影响,Western blot、免疫荧光、核浆分离及免疫沉淀检测Jab1过表达对p27~(kip1)的表达、亚细胞定位及功能的影响。
结果
1.免疫组化结果显示:1) NHL中Thr187磷酸化p27~(kip1)阳性率明显高于良性增生性淋巴结中(生发中心以外)的表达水平。结合临床资料分析显示:Thr187磷酸化p27~(kip1)与NHL病人的年龄、临床分期有相关性。病人年龄越大,临床分期越晚,其阳性率越高;与NHL病人性别、淋巴结转移情况无明显相关性。相关分析显示:Thr187磷酸化p27~(kip1)与Ki-67表达呈正相关(rs = 0.639,P<0.001);Thr187磷酸化p27~(kip1)与Skp2表达呈正相关(rs= 0.594,P<0.001);Thr187磷酸化p27~(kip1)与p27~(kip1)的表达呈正相关(rs = 0.175,P<0.001)。生存分析显示:Thr187p27~(kip1)磷酸化阳性(>10%)的病人,其五年生存率明显低于阴性(≤10%)的病人(P < 0.001)。2) Ser10磷酸化p27~(kip1)、Jab1蛋白阳性率均明显高于良性增生性淋巴结中(生发中心以外)的表达水平。结合临床资料分析显示:Ser10磷酸化p27~(kip1)、Jab1蛋白表达与NHL临床分期有相关性。与NHL病人年龄、性别、淋巴结转移情况无明显相关性。相关分析显示:Ser10磷酸化p27~(kip1)与Ki-67表达无明显相关性;Ser10磷酸化p27~(kip1)与Jab1表达呈正相关(rs= 0.696,P<0.001);Ser10磷酸化p27~(kip1)与p27~(kip1)的表达呈负相关(rs = -0.457,P<0.001);Jab1蛋白与增殖指标Ki-67表达呈正相关(rs = 0.870,P<0.001);Jab1蛋白与p27~(kip1)蛋白表达呈明显负相关(rs = -0.380,P<0.001)。生存分析显示:Ser10磷酸化p27~(kip1)阳性(>10%)、Jab1阳性(>10%)的病人,其五年生存率均明显低于阴性(≤10%)的病人(P < 0.001)。
2.构建pcDNA3.1-Myc-Jab1正义表达质粒,通过酶切电泳分析及DNA测序的方法对重组表达质粒进行鉴定,证实构建成功。
3.血清饥饿合并释放能够刺激淋巴瘤细胞同步化生长,随着细胞周期进程:1)Thr187磷酸化p27~(kip1)表达增加,并且主要位于胞核内;p27~(kip1)对cyclinE/CDK2复合物抑制作用减弱,CDK2激酶活性增强。2)Ser10磷酸化p27~(kip1)与Jab1表达明显增加;Jab1过表达导致p27~(kip1)磷酸化形式改变,胞浆分布增多,与CDK分子的亲和能力改变,最终促进细胞进入S期。
结论
1. p27~(kip1)Thr187、Ser10两个位点的磷酸化异常与NHL病例恶性程度密切相关。提示:p27~(kip1)Thr187、Ser10两个磷酸化位点可能分别通过不同途径使p27~(kip1)表达及功能发生异常,导致细胞周期失控并促进细胞异常增殖,从而参与了NHL的发生和发展。
2.成功构建了人类Jab1正义表达质粒,为进一步探讨Jab1基因在NHL发生发展中的作用奠定了实验基础。
3.在细胞水平,Thr187磷酸化p27~(kip1)可能通过泛素-蛋白酶体途径影响p27~(kip1)的降解,而Ser10磷酸化p27~(kip1)与Jab1从介导p27~(kip1)出核这一途径影响p27~(kip1)的核内外分布,两个磷酸化位点通过各自的功能特点调节p27~(kip1)的表达及功能,从而参与对淋巴瘤细胞生长的调控。
Objectives
1. To investigate the expressions of 2 major phosphorylation formats of p27~(kip1) respectively and its relative protein S-phase kinase-associated protein 2(Skp2) and Jun activation domain binding protein 1 (Jab1) in human non-Hodgkin’s Lymphomas and their clinicopathologic significance.
2. To evaluate the specific effects of pThr187p27~(kip1) and pSer10p27~(kip1) during lymphoma cell growth.
Methods
1. Immunohistochemical technique was used to detect the expression levels of pThr187p27~(kip1), pSer10p27~(kip1)p27~(kip1), Skp2, Jab1 and Ki-67 in 116 cases of NHLs and 15 cases of reactive lymphoid tissue. The NHL cases characterized in this study were universal in oriental included: 11 follicular lymphomas (FL), 7 mucosa-associated lymphoid tissue B cell lymphomas (MALT), 37 diffuse large B-cell lymphomas (DLBCL), 49 Nasal natural killer (NK)/T-cell lymphomas and 12 unspecified peripheral T-cell lymphomas (PT-un).
2. Human Jab1 complete cDNA was amplified by RT-PCR method, and was reconstructed into the eukaryotic expressive vector pcDNA3.1-Myc to form the Jab1 sense expressive plasmid. The reconstructed DNA was identified by enzyme digestion and DNA sequencing.
3. Serum starvation and release used to synchronize lymphoma cells. Flow cytometer was used to analyze cell-cycles. The expression and subcellular localization of pThr187p27~(kip1), pSer10p27~(kip1), Skp2 and Jab1 were detected by western blot, immunoflurescence and subcellular fractionation. Transfection was performed using lipofectamine 2000 transfection reagent according to the manufacture’s protocol. The cells were harvested 48 h after transfection and cell-cycles were detected by Flow cytometry. The expression and subcellular localization of Jab1, p27~(kip1) and p-Ser10p27~(kip1) were investigated by western blot, immunoflurescence, immunoprecipitation and subcellular fractionation.
Results
1. Immunohistochemistry analysis showed: 1) The expression level of pThr187p27~(kip1) in NHLs was higher than that in reactive lymphoid tissues (except germinal center). Using a 10% cutoff for pThr187p27~(kip1) expression, pThr187p27~(kip1) positive expression was significantly associated with patients’age and clinical stage, but it was not associated with patients’sex and lymph node metastasis. In all cases of NHLs analyzed, pThr187p27~(kip1) expression did correlate with expression of Skp2 (rs =0.594, P<0.001) and p27~(kip1) (rs =0.175, P=0.062) as well as Ki-67 (rs =0.639, P<0.001). By using the Kaplan-Meier analysis, patients with pThr187p27~(kip1)-positive tumor were significantly associated with short overall survival (P < 0.001). 2) The expression levels of pSer10p27~(kip1) and Jab1 in NHLs were higher than that in reactive lymphoid tissues (except germinal center). Using a 10% for cutoff, pSer10p27~(kip1) and Jab1 overexpression were both significantly associated with advanced stage, but they were not associated with patients’age, sex and lymph node metastasis. As continuous variables, pSer10p27~(kip1) expression did positively correlated with expression of Jab1(rs= 0.696, P<0.001) and negatively correlated with expression of p27~(kip1) (rs = -0.457,P<0.001); Jab1 expression was negatively associated with p27~(kip1) expression (rs = -0.380, P <0.001) and was positively associated with Ki-67 expression (rs = 0.870, P < 0.001) in all cases of NHLs analyzed. Survival analysis indicated that patients with pSer10p27~(kip1) or Jab1-positive tumor were significantly associated with short overall survival (P < 0.001).
2. The cloned DNA was confirmed to be human Jab1 cDNA.
3. Advances in the cell cycle study have revealed: 1) pThr187p27~(kip1) increased as the cells were treated with serum addition as well as the same kinetics were observed at cyclin E and CDK2. Subcellular fractionation showed that pThr187p27~(kip1) was mainly present in the nucleus of cells released from G1, leading to the dramatically reduced p27~(kip1) accumulation. Immunoprecipitation studies suggested that the enhancement of phosphorylation at Thr187 of p27~(kip1) mainly occurred in the CDK2/CyclinE complex. 2) pSer10p27~(kip1) and Jab1 were also cell-cycle dependent, being present in proliferating cells but undetectable in G1 cells. We’ve found that overexpression of Jab1 could increasing the Ser10 and Thr157 phosphorylation of p27~(kip1) while the Thr187 phosphorylation was significantly decreased. Our preliminary data demonstrated a significant decrease of p27~(kip1) expression level and a significant increase of S phase of the cell cycle in NHL cell lines that overexpressed Jab1. Immunoprecipitation studies suggested that Jab1 could change in p27~(kip1) binding preferences to CDKs and relatively major p27~(kip1)preferentially bound to CDK4.
Conclusions
1. Increased expression levels of pThr187p27~(kip1) and pSer10-p27~(kip1) were closely correlated with the aggressiveness of NHLs. Both 2 major phosphrylation formats may influence the expression and function of p27~(kip1) through different pathways, thus may play key roles in the occurrence and development of NHLs.
2. We successfully cloned human Jab1 gene and constructed its eukaryotic expressive plasmid, which was an ideal model for further study.
3. Since Thr187 phosphorylation is required for p27~(kip1) ubiquitination and Ser10 phosphorylation is necessary for the nuclear export of the protein mediated by the exportin Jab1, both phosphorylation formats may be involved in the control of the G1-S transition and have oncogenic potential.
引文
1. Chu I, Sun J, Arnaout A, et al. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 128(2), 2007, 241-244.
2. Lloyd RV, Erickson LA, Jin L, et al. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2), 1999, 313-323.
3. Ferreri AJ, Ponzoni M, Pruneri G, et al. Immunoreactivity for p27Kip1 and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin's lymphoma. Int J Cancer 94(4), 2001, 599-604.
4. Chiarle R, Budel LM, Skolnik J, et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95(2), 2000, 619-626.
5. Hara T, Kamura T, Nakayama K, et al. Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem 276(52), 2001, 48937-48943.
6. Guan X, Chen L, Wang J, et al. Mutations of phosphorylation sites Ser10 and Thr187 of p27Kip1 abolish cytoplasmic redistribution but do not abrogate G0/1 phase arrest in the HepG2 cell line. Biochem Biophys Res Commun 347(3), 2006, 601-607.
7. Rassidakis GZ, Feretzaki M, Atwell C, et al. Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105(5), 2005, 827-829.
8. Sarek G, Jarviluoma A, Ojala PM. KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. Blood 107(2), 2006, 725-732.
9. Gloghini A, Gaidano G, Larocca LM, et al. Expression of Cyclin-Dependent Kinase Inhibitor p27Kip1 in AIDS-Related Diffuse Large-Cell Lymphomas Is Associated with Epstein-Barr Virus-Encoded Latent Membrane Protein 1. Am J Pathol 161(1), 2002, 163-171.
10.黎岳南,蒋洁,郑晖. P27kip1和cyclinD1蛋白在非霍奇金淋巴瘤中的表达及意义.中国医师杂志5(10), 2003, 1320-1323.
11.程纯,张冬梅,沈爱国,等. p27kip1和Ki67蛋白在非霍奇金淋巴瘤中的表达及其临床意义.实用肿瘤杂志, 19(5), 2004, 382-385.
12. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27kip1. EMBO J 16(17), 1997, 5334-5344.
13. Chiarle R, Fan Y, Piva R, et al. S-Phase Kinase-Associated Protein 2 Expression in Non-Hodgkin’s Lymphoma Inversely Correlates with p27 Expression and Defines Cells in S Phase. Am J Pathol 160(4), 2002, 1457-1466.
1. Ferreri AJ, Ponzoni M, Pruneri G, et al. Immunoreactivity for p27Kip1 and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin's lymphoma. Int J Cancer 94(4), 2001, 599-604.
2. Erickson LA. P27kip1 and other cell-cycle protein expression in normal and neoplastic endocrine tissues. Endocr Pathol 11(2), 2000, 109-122.
3. Rodier G, Montagnoli A, Marcotullio LD, et al. p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20(23), 2001, 6672-6682.
4. Ishida N, Hara T, Kamura T, et al. Phosphotylation of p27kip1 on Serine 10 Is Required for Its Binding to CRM1 and Nuclear Export. J Biol Chem 277(17), 2002, 14355-14358.
5. Chamovitz DA, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep 2(2), 2001, 96-101.
6. Claret FX, Hibi M, Dhut S, et al. A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 383(6599), 1996, 453-457.
7. Tomoda K, Kubota Y, Arata Y, et al. The Cytoplasmic Shuttling and Subsequent Degradation of p27Kip1 Mediated by Jab1/CSN5 and the COP9 Signalosome Complex. J Biol Chem 277(3), 2002, 2302-2310.
8. Daelemans D, Costes SV, Lockett S, et al. Kinetic and Molecular Analysis of Nuclear Export Factor CRM1 Association with Its Cargo In Vivo. Mol Cell Biol 25(2), 2005, 728-739.
9. Guan X, Chen L, Wang J, et al. Mutations of phosphorylation sites Ser10 and Thr187 of p27Kip1 abolish cytoplasmic redistribution but do not abrogate G0/1 phase arrest in the HepG2 cell line. Biochem Biophys Res Commun 347(3), 2006, 601-607.
10. Kouvaraki MA, Korapati AL, Rassidakis GZ, et al. Potential Role of Jun Activation Domain-Binding Protein 1 as a Negative Regulator of p27kip1 in Pancreatic Adenocarcinoma. Cancer Res 66(17), 2006,8581-8589.
11. Sui L, Do9-p/ng Y, Ohno M, et al. Jab1 expression is associated with inverse expression of p27(kip1) and poor prognosis in epithelial ovarian tumors. Clin Cancer Res 7(12), 2001, 4130-4135.
12. Rassidakis GZ, Claret FX, Lai R, et al. Expression of p27(Kip1) and c-Jun activation binding protein 1 are inversely correlated in systemic anaplastic large cell lymphoma. Clin Cancer Res 9(3), 2003, 1121-1128.
13. Sanchez-Beato M, Camacho FI, Martinez-Montero JC, et al. Anomalous high p27KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1-cyclinD3 colocalization in tumor cells. Blood 94(2), 1999, 765-772.
14.张冬梅,陆建新,沈爱国,等. P27kip1与cyclinD3在非霍奇金淋巴瘤中的表达、定位及相互关系.中华血液学杂志26(12), 2005,723-727.
15. Viqlietto G , Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibiton of the cyclin-dependent kinase inhibitor p27kip1 by PKB/AKt-mediated phosphorylation in breast cance. Nat Med 2002, 8(10), 1136-1144.
16. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398(6723), 1999, 160-165.
17. Liang J, Zubovitz J, Petrocelli T, et al. PKB/AKT phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8(10), 2002, 1153-1160.
18. Shin I, Yakes MF, Rojo F, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27kip1 at threonine 157 and modulation of its cellular localization. Nat Med 8(10), 2002, 1145-1152.
19. Lenferink AE, Busse D, Flanagan WM, et al. ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res 61(17), 2001, 6583-6591.
20. Zhang W, Bergamaschi D, Jin B, et al. Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. Blood 105(9), 2005, 3691-3698.
1. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1(3), 2001, 222-231.
2. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9(10), 1995, 1149-1163.
3. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12), 1999, 1501-1512.
4. Erlanson, M, Portin, C, Linderholm, B, et al. Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas-prognostic implications. Blood 92(3), 1998, 770-777.
5. Zhang W, Bergamaschi D, Jin B, et al. Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. Blood 105(9), 2005, 3691-3698.
6. Chu I, Sun J, Arnaout A, et al. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 128(2), 2007, 241-244.
7. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27kip1. EMBO J 16(17), 1997, 5334-5344.
8. Guan X, Chen L, Wang J, et al. Mutations of phosphorylation sites Ser10 and Thr187 of p27Kip1 abolish cytoplasmic redistribution but do not abrogate G0/1 phase arrest in the HepG2 cell line. Biochem Biophys Res Commun 347(3), 2006, 601-607.
9. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78(1), 1994, 59-66.
10. Ponce-castaneda MV, Lee MH, Latres E, et al. p27Kip1 : Chromo2 somal mapping to 12p12 - 12p13. 1 and absence of mutations in human tumors. Cancer Res 55(6), 1995, 1211 - 1214.
11. Polyak K, Kato JY, Solomon MJ, et al. p27kip1, a cyclin-cdkinhibitor , links transforming growth factor-βand contact inhibition to cell cycle arrest. Genes Dev, 8 (1), 1994, 9 - 22.
12. Pooh RY, Toyoshima H, Hunter T, et al. Redistribution of the CDK inhibitor p27 between different cyclin CDK complexes in the mouse fibroblast cell cycle and in cells arrsted with lovastatin or ultraviolet irradiation. Mol Biol Cel1 6(9), 1995, 1197-1213.
13. Kawamata N, Morosetti R, Miller CW, et a1. Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/kipl in human malignancies. Cancer Res 55(11), 1995, 2266-2269.
14. Yang G, Ayala G, Marzo AD, et al. Elevated Skp2 protein expression in human proste cancer: association with loss of the cyclin dependent kinase inhibitor p27 and PTEN and reduced recurrence free survival. Clin Cancer Res 8(11), 2002, 3419-3426.
15. Hoshino R, Tanimura S, Watanabe K, et al. Blockade of the extracel-lular signa-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively aclivated: up-regulation of p27(kip1). J Biol Chem 276(4), 2001, 2686-2692.
16. Gardner LB, Li Q, Park MS, et a1. Hypoxia inhibit G1/S transition through regulation of p27 expression. J Biol Chem 276(11), 2001, 7919-7926.
17. Cordon-Cardo C, Koff A, DrobnjakM, et al. Distinct altered patterns of p27 KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst 90(17), 1998, 1284-1291.
18. Tokumoto YM, Apperly JA, Gao FB, et al. Post transcripional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation. Dev Biol 245(1), 2002, 224-234.
19. Huss R, Firpo E, Deeg HJ. Stem cell factor-induced expression of p27kip1 during hematopoietic differentiation. Exp Mol Pathol 63(2), 1995, 129-134.
20. Ohtani M, Isozaki H, Fujii K, et a1. Chaos and spectral analyses of heart rate variability during head-up tilting in essential hypertension. Cancer 85(8), 1999, 1711-1718.
21. Ophascharoensuk V, Fero ML, Hughes J, et a1. The cyclin dependent kinase inhibitor p27kipl safeguards against inflammatory injury. Nat Med 4(5), 1998, 575-580.
22. Newman L, XiaW, Yang HY, et al. Correlation of p27 protein expression with HER-2/neu expression in breast cance. Mol Carcinog 30(3), 2001, 169-175.
23. Zhu JS, Wang L, Cheng GQ, et al. Apop tosis mechanisms of human gastric cancer cell line MKN-45 infected with human mutant p27. World J Gastroenterol 11(47), 2005, 7536-7540.
24. Eymin B, HauggM, Droin N, et al. p27 Kip1 induces drug resistance by preventing apoptosis up stream of cytochromec release and procaspase-3 activation in leukemic cells. Oncogene 18(7), 1999, 1411-1418.
25. Hiromura K, Pipin JW, Fero ML, et al. Modulation of apoptosis by the cyclin dependent kinase inhibitor p27 (Kip1). J Clin Invest 103(5), 1999, 597-604.
26. Katayose Y, Kin M, Bakkar AN, et al. Promoting apoptosis: A novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res 57(24), 2002, 5441-5445.
27. Ning Zhang, Brenda A, Schulman, et a1. Structure of the Cull-Rbxl-Skpl-F box-skp2 SCF ubiquitin ligase complex. Nature 416 (18), 2002, 703-709.
28. Kamura T, Ham T, Kotoshiba S, et a1. Degradation of p57 mediated by SCF-dependent ubiquitylation. Proceedings of the National Acade my of Sciences of the United States of America 100(18), 2003, 10231-10236.
29. Hara T, Kamura T, Kotoshiba S, et al. Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle. Mol Cell Biol25(21), 2005, 9292-9303.
30. Kotoshiba S, Kamura T, Hara T, et al. Molecular dissection of the interaction between p27Kip1ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase. J Biol Chem 280(18), 2005, 17694-17700.
31. Kamura T, Hara T, Matsumoto M, et al. Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase. Nat Cell Biol 6(12), 2004, 1229-1235.
32. Langner C, Von WR, Ratschek M, et al. Biological significance of p27 and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and metastatic tumour tissues using a tissue microarray technique. Virchows Arch 445(6), 2004, 631-636.
33. Ben IO, Lahav BS, Meretyk S, et al. Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27kip1 in prostate cancer. J Urol 170(1), 2003, 241-245.
34. Shim EH, Johnson L, Noh HL, et al. Expression of the F-Box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Cancer Res 63(7), 2003, 1583-1588.
35. Fernandez MT, Puig L, Musulen E, et al. Prognostic significance of p27kip1, p45Skp2 and Ki67 expression profiles in Merkel cell carcinoma, extracutaneous small cell carcinoma, and cutaneous squamous cell carcinoma. Histopathology 46(6), 2005, 614-621.
36. Tamamori AM, Hayashida K, Nobori K, et al. Down regulation of p27kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4. evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation. J Biol Chem 279(48), 2004, 50429-50436.
37. Hara T, Kamura T, Nakayama K, et al. Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem 276(52), 2001, 48937-48943.
38. Chiarle R, Budel LM, Skolnik J, et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95(2), 2000, 619-626.
39. Sheaf RJ, Gmudine M, Gordon M, et a1. Cyclin E-CDK2is a regulator of p27KipI. Genes Dev 11(11), 1997, 1464-l478.
40. Wagner M, Hampel B, Hutter E, et al. Metabolic stabilization of p27kip1 in senescent fibroblasts correlates with reduced expression of the F-box protein Skp2. Exp Gerontol 37(1), 2001, 41-55.
41. Nakayama KI, Hatakeyama S, Nakayama K. Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1. Biochem Biophys Res Commun 282(4), 2001, 853-860.
42. Montagnoli A, Fiore F, Eytan E, et al. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev 13(9), 1999, 1181-1189.
43. Kudo Y, Kitajima S, Sato S, et a1. High expression of S-phase kinase-interacting protein 2,human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res 61(19), 2001, 7044-7047.
44. Claret FX, Hibi M, Dhut S, Toda T, Karin M. A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 383(6599), 1996, 453-457.
45. Aravind L, Ponting CP. Homologues of 26S proteasome subunits are regulators of transcription and translation. Protein Sci 7(5), 1998, 1250-1254.
46. Wei N, Tsuge T, Serino G, et al. The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex. Curr Biol 8(16), 1998, 919-922.
47. Kwok SF, Solano R, Tsuge T, et al. Arabidopsis homologs of a c-Jun coactivator are present both in monomeric form and in the COP9complex, and their abundance is differentially affected by the pleiotropiccop/det/fus mutations. Plant Cell 10(11), 1998, 1779-1790.
48. Kapelari B, Bech-Otschir D, Hegerl R, et al. Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome. Mol Biol 300(5), 2000, 1169-1178.
49. Seeger M, Kraft R, Ferrell K, et al. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB 12(6), 1998, 469-478.
50. Tomoda K, Kubota Y, Arata Y, et al. The Cytoplasmic Shuttling and Subsequent Degradation of p27Kip1 Mediated by Jab1/CSN5 and the COP9 Signalosome Complex.J Biol Chem 2002, 277(3), 2302-2310.
51. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398(6723), 1999, 160-165.
52. Daelemans D, Costes SV, Lockett S, et al. Kinetic and Molecular Analysis of Nuclear Export Factor CRM1 Association with Its Cargo In Vivo. Mol Cell Biol 25(2), 2005, 728-739.
53. Ishida N., Kitagawa M., Hatakeyama S., et al. Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability. J Biol Chem 275(33), 2000, 25146-25154.
54. Ishida N, Hara T, Kamura T, et al. Phosphotylation of p27kip1 on Serine 10 Is Required for Its Binding to CRM1 and Nuclear Export. J Biol Chem 277(17), 2002, 14355-14358.
55. Jeong Goo Lee and EunDuck P. Kay. Two Populations of p27 Use Differential Kinetics to Phosphorylate Ser-10 and Thr-187 via Phosphatidylinositol 3-Kinase in Response to Fibroblast Growth Factor-2 Stimulation. J Biol Chem 282(9), 2007, 6444-6454.
56. Connor MK, Kotchetkov R, Cariou S, et al. CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Mol Biol Cell 14(1), 2003, 201-213.
57. Liang J, Zubovitz J, Petrocelli T, et al. PKB/AKT phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8(10), 2002, 1153-1160.
58. Shin I, Yakes MF, Rojo F, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27kip1 at threonine 157 and modulation of its cellular localization. Nat Med 8(10), 2002, 1145-1152.
59. Viqlietto G , Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibiton of the cyclin-dependent kinase inhibitor p27kip1 by PKB/AKt-mediated phosphorylation in breast cance. Nat Med 2002, 8(10), 1136-1144.
60. Franke TF, Yang SI, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81(5), 1995, 727-736.
61. Cross DA, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559), 1995, 785-789.
62. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2(4), 2003, 339-345.
63. Alt JR, Cleveland JL, hannink M, et a1. Phosphorylation dependent regulation of cyclinD1 nuclear export and cyclinDl dependent cellular transformation. Genes Dev 2000, 14(24), 3102-3114.
64. Medema RH, Kops GJ, Bos JL, et al. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404(6779), 2000, 782-787.
65. Shin I, Rotty J, Wu FY, et al. Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry. J Biol Chem 280(7), 2005, 6055-6063.
66. Sekimoto T, Fukumoto M, Yoneda Y. 14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1). EMBO J 23(9), 2004, 1934-1942.
67. Zhang Q, Tian L, Mansouri A, et al. Inducible expression of a degradation-resistant form of p27Kip1 causes growth arrest and apoptosis in breast cancer cells. FEBS Lett 579(18), 2005, 3932-3940.
68. Koji Harada, Supriatno, Yuichiro Kawashima, et al. Down-regulation of S-phase kinase associated protein 2(Skp2) induces apoptosis in oral cancer cells. Oral Oncology 41(6), 2005, 623-630.
2. Lloyd RV, Erickson LA, Jin L, et al. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2), 1999, 313-323.
3. Ferreri AJ, Ponzoni M, Pruneri G, et al. Immunoreactivity for p27Kip1 and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin's lymphoma. Int J Cancer 94(4), 2001, 599-604.
4. Chiarle R, Budel LM, Skolnik J, et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95(2), 2000, 619-626.
5. Hara T, Kamura T, Nakayama K, et al. Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem 276(52), 2001, 48937-48943.
6. Guan X, Chen L, Wang J, et al. Mutations of phosphorylation sites Ser10 and Thr187 of p27Kip1 abolish cytoplasmic redistribution but do not abrogate G0/1 phase arrest in the HepG2 cell line. Biochem Biophys Res Commun 347(3), 2006, 601-607.
7. Rassidakis GZ, Feretzaki M, Atwell C, et al. Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105(5), 2005, 827-829.
8. Sarek G, Jarviluoma A, Ojala PM. KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. Blood 107(2), 2006, 725-732.
9. Gloghini A, Gaidano G, Larocca LM, et al. Expression of Cyclin-Dependent Kinase Inhibitor p27Kip1 in AIDS-Related Diffuse Large-Cell Lymphomas Is Associated with Epstein-Barr Virus-Encoded Latent Membrane Protein 1. Am J Pathol 161(1), 2002, 163-171.
10.黎岳南,蒋洁,郑晖. P27kip1和cyclinD1蛋白在非霍奇金淋巴瘤中的表达及意义.中国医师杂志5(10), 2003, 1320-1323.
11.程纯,张冬梅,沈爱国,等. p27kip1和Ki67蛋白在非霍奇金淋巴瘤中的表达及其临床意义.实用肿瘤杂志, 19(5), 2004, 382-385.
12. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27kip1. EMBO J 16(17), 1997, 5334-5344.
13. Chiarle R, Fan Y, Piva R, et al. S-Phase Kinase-Associated Protein 2 Expression in Non-Hodgkin’s Lymphoma Inversely Correlates with p27 Expression and Defines Cells in S Phase. Am J Pathol 160(4), 2002, 1457-1466.
1. Ferreri AJ, Ponzoni M, Pruneri G, et al. Immunoreactivity for p27Kip1 and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin's lymphoma. Int J Cancer 94(4), 2001, 599-604.
2. Erickson LA. P27kip1 and other cell-cycle protein expression in normal and neoplastic endocrine tissues. Endocr Pathol 11(2), 2000, 109-122.
3. Rodier G, Montagnoli A, Marcotullio LD, et al. p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20(23), 2001, 6672-6682.
4. Ishida N, Hara T, Kamura T, et al. Phosphotylation of p27kip1 on Serine 10 Is Required for Its Binding to CRM1 and Nuclear Export. J Biol Chem 277(17), 2002, 14355-14358.
5. Chamovitz DA, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep 2(2), 2001, 96-101.
6. Claret FX, Hibi M, Dhut S, et al. A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 383(6599), 1996, 453-457.
7. Tomoda K, Kubota Y, Arata Y, et al. The Cytoplasmic Shuttling and Subsequent Degradation of p27Kip1 Mediated by Jab1/CSN5 and the COP9 Signalosome Complex. J Biol Chem 277(3), 2002, 2302-2310.
8. Daelemans D, Costes SV, Lockett S, et al. Kinetic and Molecular Analysis of Nuclear Export Factor CRM1 Association with Its Cargo In Vivo. Mol Cell Biol 25(2), 2005, 728-739.
9. Guan X, Chen L, Wang J, et al. Mutations of phosphorylation sites Ser10 and Thr187 of p27Kip1 abolish cytoplasmic redistribution but do not abrogate G0/1 phase arrest in the HepG2 cell line. Biochem Biophys Res Commun 347(3), 2006, 601-607.
10. Kouvaraki MA, Korapati AL, Rassidakis GZ, et al. Potential Role of Jun Activation Domain-Binding Protein 1 as a Negative Regulator of p27kip1 in Pancreatic Adenocarcinoma. Cancer Res 66(17), 2006,8581-8589.
11. Sui L, Do9-p/ng Y, Ohno M, et al. Jab1 expression is associated with inverse expression of p27(kip1) and poor prognosis in epithelial ovarian tumors. Clin Cancer Res 7(12), 2001, 4130-4135.
12. Rassidakis GZ, Claret FX, Lai R, et al. Expression of p27(Kip1) and c-Jun activation binding protein 1 are inversely correlated in systemic anaplastic large cell lymphoma. Clin Cancer Res 9(3), 2003, 1121-1128.
13. Sanchez-Beato M, Camacho FI, Martinez-Montero JC, et al. Anomalous high p27KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1-cyclinD3 colocalization in tumor cells. Blood 94(2), 1999, 765-772.
14.张冬梅,陆建新,沈爱国,等. P27kip1与cyclinD3在非霍奇金淋巴瘤中的表达、定位及相互关系.中华血液学杂志26(12), 2005,723-727.
15. Viqlietto G , Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibiton of the cyclin-dependent kinase inhibitor p27kip1 by PKB/AKt-mediated phosphorylation in breast cance. Nat Med 2002, 8(10), 1136-1144.
16. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398(6723), 1999, 160-165.
17. Liang J, Zubovitz J, Petrocelli T, et al. PKB/AKT phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8(10), 2002, 1153-1160.
18. Shin I, Yakes MF, Rojo F, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27kip1 at threonine 157 and modulation of its cellular localization. Nat Med 8(10), 2002, 1145-1152.
19. Lenferink AE, Busse D, Flanagan WM, et al. ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res 61(17), 2001, 6583-6591.
20. Zhang W, Bergamaschi D, Jin B, et al. Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. Blood 105(9), 2005, 3691-3698.
1. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1(3), 2001, 222-231.
2. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9(10), 1995, 1149-1163.
3. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12), 1999, 1501-1512.
4. Erlanson, M, Portin, C, Linderholm, B, et al. Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas-prognostic implications. Blood 92(3), 1998, 770-777.
5. Zhang W, Bergamaschi D, Jin B, et al. Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. Blood 105(9), 2005, 3691-3698.
6. Chu I, Sun J, Arnaout A, et al. p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 128(2), 2007, 241-244.
7. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27kip1. EMBO J 16(17), 1997, 5334-5344.
8. Guan X, Chen L, Wang J, et al. Mutations of phosphorylation sites Ser10 and Thr187 of p27Kip1 abolish cytoplasmic redistribution but do not abrogate G0/1 phase arrest in the HepG2 cell line. Biochem Biophys Res Commun 347(3), 2006, 601-607.
9. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78(1), 1994, 59-66.
10. Ponce-castaneda MV, Lee MH, Latres E, et al. p27Kip1 : Chromo2 somal mapping to 12p12 - 12p13. 1 and absence of mutations in human tumors. Cancer Res 55(6), 1995, 1211 - 1214.
11. Polyak K, Kato JY, Solomon MJ, et al. p27kip1, a cyclin-cdkinhibitor , links transforming growth factor-βand contact inhibition to cell cycle arrest. Genes Dev, 8 (1), 1994, 9 - 22.
12. Pooh RY, Toyoshima H, Hunter T, et al. Redistribution of the CDK inhibitor p27 between different cyclin CDK complexes in the mouse fibroblast cell cycle and in cells arrsted with lovastatin or ultraviolet irradiation. Mol Biol Cel1 6(9), 1995, 1197-1213.
13. Kawamata N, Morosetti R, Miller CW, et a1. Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/kipl in human malignancies. Cancer Res 55(11), 1995, 2266-2269.
14. Yang G, Ayala G, Marzo AD, et al. Elevated Skp2 protein expression in human proste cancer: association with loss of the cyclin dependent kinase inhibitor p27 and PTEN and reduced recurrence free survival. Clin Cancer Res 8(11), 2002, 3419-3426.
15. Hoshino R, Tanimura S, Watanabe K, et al. Blockade of the extracel-lular signa-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively aclivated: up-regulation of p27(kip1). J Biol Chem 276(4), 2001, 2686-2692.
16. Gardner LB, Li Q, Park MS, et a1. Hypoxia inhibit G1/S transition through regulation of p27 expression. J Biol Chem 276(11), 2001, 7919-7926.
17. Cordon-Cardo C, Koff A, DrobnjakM, et al. Distinct altered patterns of p27 KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst 90(17), 1998, 1284-1291.
18. Tokumoto YM, Apperly JA, Gao FB, et al. Post transcripional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation. Dev Biol 245(1), 2002, 224-234.
19. Huss R, Firpo E, Deeg HJ. Stem cell factor-induced expression of p27kip1 during hematopoietic differentiation. Exp Mol Pathol 63(2), 1995, 129-134.
20. Ohtani M, Isozaki H, Fujii K, et a1. Chaos and spectral analyses of heart rate variability during head-up tilting in essential hypertension. Cancer 85(8), 1999, 1711-1718.
21. Ophascharoensuk V, Fero ML, Hughes J, et a1. The cyclin dependent kinase inhibitor p27kipl safeguards against inflammatory injury. Nat Med 4(5), 1998, 575-580.
22. Newman L, XiaW, Yang HY, et al. Correlation of p27 protein expression with HER-2/neu expression in breast cance. Mol Carcinog 30(3), 2001, 169-175.
23. Zhu JS, Wang L, Cheng GQ, et al. Apop tosis mechanisms of human gastric cancer cell line MKN-45 infected with human mutant p27. World J Gastroenterol 11(47), 2005, 7536-7540.
24. Eymin B, HauggM, Droin N, et al. p27 Kip1 induces drug resistance by preventing apoptosis up stream of cytochromec release and procaspase-3 activation in leukemic cells. Oncogene 18(7), 1999, 1411-1418.
25. Hiromura K, Pipin JW, Fero ML, et al. Modulation of apoptosis by the cyclin dependent kinase inhibitor p27 (Kip1). J Clin Invest 103(5), 1999, 597-604.
26. Katayose Y, Kin M, Bakkar AN, et al. Promoting apoptosis: A novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res 57(24), 2002, 5441-5445.
27. Ning Zhang, Brenda A, Schulman, et a1. Structure of the Cull-Rbxl-Skpl-F box-skp2 SCF ubiquitin ligase complex. Nature 416 (18), 2002, 703-709.
28. Kamura T, Ham T, Kotoshiba S, et a1. Degradation of p57 mediated by SCF-dependent ubiquitylation. Proceedings of the National Acade my of Sciences of the United States of America 100(18), 2003, 10231-10236.
29. Hara T, Kamura T, Kotoshiba S, et al. Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle. Mol Cell Biol25(21), 2005, 9292-9303.
30. Kotoshiba S, Kamura T, Hara T, et al. Molecular dissection of the interaction between p27Kip1ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase. J Biol Chem 280(18), 2005, 17694-17700.
31. Kamura T, Hara T, Matsumoto M, et al. Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase. Nat Cell Biol 6(12), 2004, 1229-1235.
32. Langner C, Von WR, Ratschek M, et al. Biological significance of p27 and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and metastatic tumour tissues using a tissue microarray technique. Virchows Arch 445(6), 2004, 631-636.
33. Ben IO, Lahav BS, Meretyk S, et al. Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27kip1 in prostate cancer. J Urol 170(1), 2003, 241-245.
34. Shim EH, Johnson L, Noh HL, et al. Expression of the F-Box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Cancer Res 63(7), 2003, 1583-1588.
35. Fernandez MT, Puig L, Musulen E, et al. Prognostic significance of p27kip1, p45Skp2 and Ki67 expression profiles in Merkel cell carcinoma, extracutaneous small cell carcinoma, and cutaneous squamous cell carcinoma. Histopathology 46(6), 2005, 614-621.
36. Tamamori AM, Hayashida K, Nobori K, et al. Down regulation of p27kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4. evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation. J Biol Chem 279(48), 2004, 50429-50436.
37. Hara T, Kamura T, Nakayama K, et al. Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem 276(52), 2001, 48937-48943.
38. Chiarle R, Budel LM, Skolnik J, et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95(2), 2000, 619-626.
39. Sheaf RJ, Gmudine M, Gordon M, et a1. Cyclin E-CDK2is a regulator of p27KipI. Genes Dev 11(11), 1997, 1464-l478.
40. Wagner M, Hampel B, Hutter E, et al. Metabolic stabilization of p27kip1 in senescent fibroblasts correlates with reduced expression of the F-box protein Skp2. Exp Gerontol 37(1), 2001, 41-55.
41. Nakayama KI, Hatakeyama S, Nakayama K. Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1. Biochem Biophys Res Commun 282(4), 2001, 853-860.
42. Montagnoli A, Fiore F, Eytan E, et al. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev 13(9), 1999, 1181-1189.
43. Kudo Y, Kitajima S, Sato S, et a1. High expression of S-phase kinase-interacting protein 2,human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res 61(19), 2001, 7044-7047.
44. Claret FX, Hibi M, Dhut S, Toda T, Karin M. A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 383(6599), 1996, 453-457.
45. Aravind L, Ponting CP. Homologues of 26S proteasome subunits are regulators of transcription and translation. Protein Sci 7(5), 1998, 1250-1254.
46. Wei N, Tsuge T, Serino G, et al. The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex. Curr Biol 8(16), 1998, 919-922.
47. Kwok SF, Solano R, Tsuge T, et al. Arabidopsis homologs of a c-Jun coactivator are present both in monomeric form and in the COP9complex, and their abundance is differentially affected by the pleiotropiccop/det/fus mutations. Plant Cell 10(11), 1998, 1779-1790.
48. Kapelari B, Bech-Otschir D, Hegerl R, et al. Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome. Mol Biol 300(5), 2000, 1169-1178.
49. Seeger M, Kraft R, Ferrell K, et al. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB 12(6), 1998, 469-478.
50. Tomoda K, Kubota Y, Arata Y, et al. The Cytoplasmic Shuttling and Subsequent Degradation of p27Kip1 Mediated by Jab1/CSN5 and the COP9 Signalosome Complex.J Biol Chem 2002, 277(3), 2302-2310.
51. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398(6723), 1999, 160-165.
52. Daelemans D, Costes SV, Lockett S, et al. Kinetic and Molecular Analysis of Nuclear Export Factor CRM1 Association with Its Cargo In Vivo. Mol Cell Biol 25(2), 2005, 728-739.
53. Ishida N., Kitagawa M., Hatakeyama S., et al. Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability. J Biol Chem 275(33), 2000, 25146-25154.
54. Ishida N, Hara T, Kamura T, et al. Phosphotylation of p27kip1 on Serine 10 Is Required for Its Binding to CRM1 and Nuclear Export. J Biol Chem 277(17), 2002, 14355-14358.
55. Jeong Goo Lee and EunDuck P. Kay. Two Populations of p27 Use Differential Kinetics to Phosphorylate Ser-10 and Thr-187 via Phosphatidylinositol 3-Kinase in Response to Fibroblast Growth Factor-2 Stimulation. J Biol Chem 282(9), 2007, 6444-6454.
56. Connor MK, Kotchetkov R, Cariou S, et al. CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Mol Biol Cell 14(1), 2003, 201-213.
57. Liang J, Zubovitz J, Petrocelli T, et al. PKB/AKT phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8(10), 2002, 1153-1160.
58. Shin I, Yakes MF, Rojo F, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27kip1 at threonine 157 and modulation of its cellular localization. Nat Med 8(10), 2002, 1145-1152.
59. Viqlietto G , Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibiton of the cyclin-dependent kinase inhibitor p27kip1 by PKB/AKt-mediated phosphorylation in breast cance. Nat Med 2002, 8(10), 1136-1144.
60. Franke TF, Yang SI, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81(5), 1995, 727-736.
61. Cross DA, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559), 1995, 785-789.
62. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2(4), 2003, 339-345.
63. Alt JR, Cleveland JL, hannink M, et a1. Phosphorylation dependent regulation of cyclinD1 nuclear export and cyclinDl dependent cellular transformation. Genes Dev 2000, 14(24), 3102-3114.
64. Medema RH, Kops GJ, Bos JL, et al. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404(6779), 2000, 782-787.
65. Shin I, Rotty J, Wu FY, et al. Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry. J Biol Chem 280(7), 2005, 6055-6063.
66. Sekimoto T, Fukumoto M, Yoneda Y. 14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1). EMBO J 23(9), 2004, 1934-1942.
67. Zhang Q, Tian L, Mansouri A, et al. Inducible expression of a degradation-resistant form of p27Kip1 causes growth arrest and apoptosis in breast cancer cells. FEBS Lett 579(18), 2005, 3932-3940.
68. Koji Harada, Supriatno, Yuichiro Kawashima, et al. Down-regulation of S-phase kinase associated protein 2(Skp2) induces apoptosis in oral cancer cells. Oral Oncology 41(6), 2005, 623-630.