Prohibitin facilitates cellular senescence by recruiting specific corepressors to inhibit E2F target genes
Prohibitin facilitates cellular senescence by recruiting specific corepressors to inhibit E2F target genes
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DOI：
10.1128/mcb.02142-05
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发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Chellappan, Srikurnar
中科院分区：
文献类型：
--
作者：
Rastogi, Shipra;Joshi, Bharat.;Chellappan, Srikurnar
Prohibitin是一种生长调节基因，在细胞核、线粒体和细胞质中具有多效性功能。早期的研究提出了抑制素在调节细胞衰老中的作用，但其潜在的机制仍然未知。在这里，我们表明，衰老诱导的DNA损伤剂导致本地化的抑制素特定的异染色质病灶。Prohibitin可与异染色质蛋白1（HP 1）家族蛋白结合，并与HP 1 γ共定位于衰老相关的异染色质灶中。此外，HP 1 γ可以协同抑制抑制素抑制E2 F1介导的转录活性。通过小干扰RNA或反义技术耗尽抑制素导致衰老表型减少，与衰老相关的β-半乳糖苷酶表达减少和衰老相关异染色质病灶数量减少相关。染色质免疫沉淀试验表明，需要抑制素的招聘HP 1 γ E2 F1调节的增殖启动子，导致其镇压。抑制素的消融阻止了衰老时HPI γ而不是Suv 39 H向启动子的募集。抑制素介导的招聘HP 1 γ只发生在衰老细胞，而不是在静止细胞，因此，有一个二分法的不同corepressors的招聘抑制素，这取决于生长停滞的类型。这些研究表明，抑制素在诱导细胞衰老中起着重要作用。
Prohibitin is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria, and cytoplasmic compartments. Earlier studies had proposed a role for prohibitin in modulating cellular senescence, but the underlying mechanisms remain unknown. Here we show that senescence induced by DNA-damaging agents causes the localization of prohibitin to specific heterochromatic foci. Prohibitin could bind to heterochromatin protein 1 (HP1) family proteins and colocalized with HP1 gamma in senescence-associated heterochromatic foci. Further, HP1 gamma could synergize with prohibitin to repress E2F1-mediated transcriptional activity. The depletion of prohibitin by small interfering RNA or antisense techniques led to a reduction in the senescent phenotype, correlating with a reduced expression of senescence-associated P-galactosidase and fewer numbers of senescence-associated heterochromatic foci. Chromatin immunoprecipitation assays showed that prohibitin is needed for the recruitment of HP1 gamma to E2F1-regulated proliferative promoters, leading to their repression. The ablation of prohibitin prevented the recruitment of HPI gamma, but not Suv39H, to the promoters upon senescence. Prohibitin-mediated recruitment of HP1 gamma occurred in only senescent cells, not in quiescent cells; thus, there is a dichotomy in the recruitment of different corepressors by prohibitin, depending on the type of growth arrest. These studies show that prohibitin plays a vital role in inducing cellular senescence.