Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation
Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation
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DOI：
10.1038/onc.2014.322
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发表时间：
2015-07-01
期刊：
影响因子：
8
通讯作者：
David, G.
中科院分区：
文献类型：
--
作者：
DiMauro, T.;Cantor, D. J.;David, G.
Polycomb族蛋白Bmi-1是细胞衰老的重要调节因子，据信主要通过直接抑制Ink 4a/Arf基因座发挥作用。然而，Ink 4a/Arf的同时缺失并不能完全挽救在Bmi-1（-/-）小鼠中检测到的缺陷，这表明其他的Bmi-1靶标仍有待鉴定。染色质相关的Sin 3B蛋白的表达受到致癌应激的刺激，并且是癌基因诱导的衰老所需的。在这里，我们表明，致癌压力导致Bmi-1从Sin 3B位点的解离，导致Sin 3B表达增加，随后进入细胞衰老。此外，Sin 3B是衰老表型和Bmi-1耗竭引起的活性氧水平升高所必需的。总之，这些结果确定Sin 3B作为Bmi-1的一种新的直接靶点，并建立Bmi-1驱动的Sin 3B抑制作为细胞衰老的重要调节因子。
The Polycomb group protein Bmi-1 is an essential regulator of cellular senescence and is believed to function largely through the direct repression of the Ink4a/Arf locus. However, concurrent deletion of Ink4a/Arf does not fully rescue the defects detected in Bmi-1(-/-) mice, indicating that additional Bmi-1 targets remain to be identified. The expression of the chromatin-associated Sin3B protein is stimulated by oncogenic stress, and is required for oncogene-induced senescence. Here we demonstrate that oncogenic stress leads to the dissociation of Bmi-1 from the Sin3B locus, resulting in increased Sin3B expression and subsequent entry into cellular senescence. Furthermore, Sin3B is required for the senescent phenotype and elevated levels of reactive oxygen species elicited upon Bmi-1 depletion. Altogether, these results identify Sin3B as a novel direct target of Bmi-1, and establish Bmi-1-driven repression of Sin3B as an essential regulator of cellular senescence.