p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes
p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes
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DOI：
10.1038/onc.2011.582
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发表时间：
2012-09-01
期刊：
影响因子：
8
通讯作者：
Bachs, O.
中科院分区：
文献类型：
--
作者：
Pippa, R.;Espinosa, L.;Bachs, O.
细胞周期蛋白依赖性激酶抑制剂p27（Kip 1）（p27）对细胞周期进程具有重要的负性作用。除了作为细胞周期蛋白-cdk抑制剂的经典作用外，它还具有非细胞周期蛋白-cdk依赖的功能，如调节细胞骨架重排和细胞运动。p27缺陷与肿瘤的侵袭性和不良的临床结果有关，尽管这种参与的潜在机制仍然不清楚。我们在这里报告了一个新的细胞功能的p27作为一个转录调节与p130/E2 F4复合物，可能是相关的肿瘤发生。我们观察到p27与参与重要细胞功能的基因的特异性启动子相关，如RNA的加工和剪接、线粒体组织和呼吸、翻译和细胞周期。在这些启动子上，p27与p130、E2 F4和作为组蛋白脱乙酰酶（HDAC）和mSIN 3A的共阻遏物共定位。p27与这些蛋白质共免疫沉淀，通过亲和层析，我们证明了p27与p130和E2 F4通过其羧基半直接相互作用。我们还表明，p130在启动子上招募p27，并且随后招募HDAC和mSIN 3A需要p27。表达微阵列和荧光素酶分析表明，p27的行为作为这些p27靶基因（p27-TG）的转录抑制因子。最后，在人类肿瘤中，我们建立了p27-TG过表达与生存率低的相关性。因此，p27作为转录抑制因子的这种新功能可能在p27水平低的肿瘤的主要侵袭性中发挥作用。Oncogene（2012）31，4207-4220; doi：10.1038/onc.2011.582; 2011年12月19日在线发表
The cyclin-cdk (cyclin-dependent kinase) inhibitor p27(Kip1) (p27) has a crucial negative role on cell cycle progression. In addition to its classical role as a cyclin-cdk inhibitor, it also performs cyclin-cdk-independent functions as the regulation of cytoskeleton rearrangements and cell motility. p27 deficiency has been associated with tumor aggressiveness and poor clinical outcome, although the mechanisms underlying this participation still remain elusive. We report here a new cellular function of p27 as a transcriptional regulator in association with p130/E2F4 complexes that could be relevant for tumorigenesis. We observed that p27 associates with specific promoters of genes involved in important cellular functions as processing and splicing of RNA, mitochondrial organization and respiration, translation and cell cycle. On these promoters p27 co-localizes with p130, E2F4 and co-repressors as histone deacetylases (HDACs) and mSIN3A. p27 co-immunoprecipitates with these proteins and by affinity chromatography, we demonstrated a direct interaction of p27 with p130 and E2F4 through its carboxyl-half. We have also shown that p130 recruits p27 on the promoters, and there p27 is needed for the subsequent recruitment of HDACs and mSIN3A. Expression microarrays and luciferase assays revealed that p27 behaves as transcriptional repressor of these p27-target genes (p27-TGs). Finally, in human tumors, we established a correlation with overexpression of p27-TGs and poor survival. Thus, this new function of p27 as a transcriptional repressor could have a role in the major aggressiveness of tumors with low levels of p27. Oncogene (2012) 31, 4207-4220; doi:10.1038/onc.2011.582; published online 19 December 2011