Wang Yuchan, Fei Min, Cheng Chun, Zhang Dongmei, Lu Jianxin, He Song, Zhao Yueming, Wang You, Shen Aiguo
Department of Immunology and Microbiology, Medical College of Nantong University, Nantong, PR China.
Cancer Biol Ther. 2008 Mar;7(3):460-7. doi: 10.4161/cbt.7.3.5456. Epub 2007 Dec 21.
Recent evidences suggest that Jun activation domain-binding protein 1 (Jab1) specifically interacts with the Cdk inhibitor p27kip1 and induces nuclear export and subsequent degradation of p27kip1. The purpose of this study is to investigate whether Jab1 expression is correlated with p27kip1 level in Non-Hodgkin's Lymphomas(NHLs) and how it influenced the stability of p27kip1, as well as whether Jab1 expression is associated with clinicopathologic variables and prognosis of NHLs.
Immunohistochemical analysis showed that Jab1 expression was negatively associated with p27kip1 level and significantly associated with unfavorable clinicopathologic variables. Overexpression Jab1 in lymphoma cell lines Jurkat resulted in decreased p27kip1 level and advanced progression from G(1) to S phase of the cell cycle. Subcellular fractionation confirmed Jab1 could lead to nuclear export of p27kip1. Phosphorylation of p27kip1 at Ser10 and Thr157 was significantly increased after Jab1 transient transfected, while Thr187 phosphorylation was decreased. Immunoprecipitation demonstrated that Jab1 overexpression facilitated p27kip1 to dissociate from Cdk2 and associated with Cdk4. Finally, Survival analysis revealed that Jab1 overexpression is significantly associated with overall survival (P = 0.000). When Jab1 and p27kip1 are combined, patients with Jab1(+)/p27kip1(-) revealed poorer overall survival (p = 0.001). Multivariate analysis revealed that Jab1 protein is an independent prognostic indicator for overall survival.
Immunohistochemical and/or Western blot analysis was done in 116 cases of NHLs and Jurkat cells.
These findings suggest that Jab1 protein may contribute to the tumor progression through Jab1-mediated p27kip1 degradation and that control of Jab1 expression is a novel therapeutic target with NHLs.
近期证据表明，Jun激活域结合蛋白1（Jab1）特异性地与细胞周期蛋白依赖性激酶抑制剂p27kip1相互作用，并诱导p27kip1的核输出及随后的降解。本研究旨在探讨Jab1表达是否与非霍奇金淋巴瘤（NHLs）中p27kip1水平相关，其如何影响p27kip1的稳定性，以及Jab1表达是否与NHLs的临床病理变量及预后相关。
免疫组织化学分析显示，Jab1表达与p27kip1水平呈负相关，且与不良临床病理变量显著相关。淋巴瘤细胞系Jurkat中Jab1的过表达导致p27kip1水平降低，并使细胞周期从G(1)期向S期进展加速。亚细胞分级分离证实Jab1可导致p27kip1的核输出。Jab1瞬时转染后，p27kip1在Ser10和Thr157位点的磷酸化显著增加，而Thr187位点的磷酸化降低。免疫沉淀表明，Jab1的过表达促进p27kip1与Cdk2解离并与Cdk4结合。最后，生存分析显示Jab1的过表达与总生存期显著相关（P = 0.000）。当Jab1和p27kip1联合分析时，Jab1(+)/p27kip1(-)的患者总生存期较差（p = 0.001）。多变量分析显示Jab1蛋白是总生存期的独立预后指标。
对116例NHLs病例和Jurkat细胞进行免疫组织化学和/或蛋白质印迹分析。
这些发现表明，Jab1蛋白可能通过Jab1介导的p27kip1降解促进肿瘤进展，且控制Jab1表达是NHLs的一个新的治疗靶点。
