Co-regulation of senescence-associated genes by oncogenic homeobox proteins and polycomb repressive complexes
Co-regulation of senescence-associated genes by oncogenic homeobox proteins and polycomb repressive complexes
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DOI：
10.4161/cc.25331
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发表时间：
2013-07-15
期刊：
影响因子：
4.3
通讯作者：
Gil, Jesus
中科院分区：
文献类型：
--
作者：
Martin, Nadine;Raguz, Selina;Gil, Jesus
细胞衰老是一种稳定的细胞周期停滞，可由端粒缩短、癌基因激活或DNA损伤等应激诱导。衰老是肿瘤发生过程中需要绕过的一个强大的抗癌屏障。细胞周期调节因子p16（INK4a）是衰老过程中上调的关键效应因子。多梳抑制复合物（PRCs）在沉默编码p16（INK4a）的INK4/ARF基因座中起着至关重要的作用，但PRCs被招募到该基因座以及其他靶点的机制尚不清楚。最近，我们发现同源盒蛋白HLX1 （h2.0样同源盒1）和HOXA9（同源盒A9）具有绕过衰老的能力。我们发现HLX1和HOXA9招募PRCs抑制INK4a，这是解释它们对衰老作用的关键机制。本研究为HLX1和HOXA9调控其他与衰老相关的PRC靶基因提供了证据。由于HLX1和HOXA9都是与白血病发生有关的致癌基因，我们讨论了同源盒蛋白和prc之间的合作对衰老和癌症的影响。
Cellular senescence is a stable cell cycle arrest that can be induced by stresses such as telomere shortening, oncogene activation or DNA damage. Senescence is a potent anticancer barrier that needs to be circumvented during tumorigenesis. The cell cycle regulator p16(INK4a) is a key effector upregulated during senescence. Polycomb repressive complexes (PRCs) play a crucial role in silencing the INK4/ARF locus, which encodes for p16(INK4a), but the mechanisms by which PRCs are recruited to this locus as well as to other targets remain poorly understood. Recently we discovered the ability of the homeobox proteins HLX1 (H2.0-like homeobox 1) and HOXA9 (Homeobox A9) to bypass senescence. We showed that HLX1 and HOXA9 recruit PRCs to repress INK4a, which constitutes a key mechanism explaining their effects on senescence. Here we provide evidence for the regulation of additional senescence-associated PRC target genes by HLX1 and HOXA9. As both HLX1 and HOXA9 are oncogenes implicated in leukemogenesis, we discuss the implications that the collaboration between Homeobox proteins and PRCs has for senescence and cancer.