A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition.
A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition.
复制标题
DOI：
10.1042/bj20140103
复制
发表时间：
2014-11-01
期刊：
影响因子：
--
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Fang Y;Wang Y;Wang Y;Meng Y;Zhu J;Jin H;Li J;Zhang D;Yu Y;Wu XR;Huang C
p27 Kip 1是一种有效的细胞周期蛋白依赖性激酶抑制剂，可驱动G1-S细胞周期转换。p27 Kip 1表达减少在广泛的人类肿瘤中普遍存在;然而，p27 Kip 1介导的肿瘤抑制的确切机制仍然不清楚。在本研究中，我们发现p27 Kip 1和EGFR（表皮生长因子受体）表达之间存在密切的负相关关系：亲本T24人膀胱癌细胞具有高p27 Kip 1表达，但低EGFR表达，与之形成鲜明对比的是，T24的转移衍生物（T24 T）具有低p27 Kip 1表达，但高EGFR表达。这种关系也被发现在各种人类癌症组织中，不仅是相关的，而且因果关系;在MEF（小鼠胚胎成纤维细胞）细胞中p27 Kip 1的耗竭导致EGFR表达显着升高，结果与Egfr启动子-荧光素酶报告在T24和MEF细胞中重现，表明EGFR的转录抑制p27 Kip 1。事实上，发现p27 Kip 1通过JNK（c-Jun N-末端激酶）/c-Jun转录因子调节EGFR表达：p27 Kip 1缺陷激活JNK/c-Jun，而显性阴性突变体抑制JNK/c-Jun显著抑制Egfr转录。此外，Egfr基因的近端启动子对其转录至关重要，其中c-Jun的募集活性在p27 Kip 1 −/−细胞中比在p27 Kip 1 +/+细胞中大得多。将GFP-p27 Kip 1导入T24 T细胞抑制JNK/c-Jun活化、EGFR表达和锚定非依赖性生长。本研究的结果表明，p27 Kip 1抑制JNK/c-Jun激活和EGFR在MEFs和人膀胱癌细胞的表达，所获得的结果是一致的，从人类癌症标本。本研究为p27 Kip 1抑制癌细胞生长、迁移和转移提供了新的见解。p27 Kip 1与EGFR在亲代T24人膀胱癌细胞和各种人癌组织中的表达呈负相关，细胞中p27 Kip 1的缺失通过JNK/c-Jun级联反应通过p27 Kip 1对Egfr的转录抑制显著提高EGFR的表达。
p27Kip1 is a potent inhibitor of cyclin-dependent kinases that drive G1-to-S cell-cycle transition. Reduced p27Kip1 expression is prevalent in a wide range of human tumours; however, the exact mechanism(s) of p27Kip1-mediated tumour suppression remains obscure. In the present study, we identified a close inverse relationship between p27Kip1 and EGFR (epidermal growth factor receptor) expression: the parental T24 human bladder cancer cells had high p27Kip1 expression but low EGFR expression and, in striking contrast, the metastatic derivative of T24 (T24T) had low p27Kip1 expression but high EGFR expression. This relationship was also found in various human cancer tissues, and was not only just correlative but also causal; depletion of p27Kip1 in MEF (mouse embryonic fibroblast) cells resulted in markedly elevated EGFR expression, a result reproducible with an Egfr promoter-luciferase reporter in both T24 and MEF cells, suggesting transcriptional repression of EGFR by p27Kip1. Indeed, p27Kip1 was found to regulate EGFR expression via the JNK (c-Jun N-terminal kinase)/c-Jun transcription factor: p27Kip1 deficiency activated JNK/c-Jun, whereas inhibition of JNK/c-Jun by dominant-negative mutants dramatically repressed Egfr transcription. Furthermore, the proximal promoter of the Egfr gene was crucial for its transcription, where the recruiting activity of c-Jun was much greater in p27Kip1−/− cells than in p27Kip1+/+ cells. Introduction of GFP–p27Kip1 into T24T cells suppressed JNK/c-Jun activation, EGFR expression and anchorage-independent growth. The results of the present study demonstrate that p27Kip1 suppresses JNK/c-Jun activation and EGFR expression in MEFs and human bladder cancer cells, and the results obtained are consistent with those from human cancer specimens. The present study provides new insights into p27Kip1 suppression of cancer cell growth, migration and metastasis. An inverse relationship between p27Kip1 and EGFR expression in parental T24 human bladder cancer cells and various human cancer tissues was found. Depletion of p27Kip1 in cells markedly elevated EGFR expression through transcriptional repression of Egfr by p27Kip1 via the JNK/c-Jun cascade.