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首页> 外文期刊>Oncogene >p21WAF1 gene promoter is epigenetically silenced by CTIP2 and SUV39H1
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p21WAF1 gene promoter is epigenetically silenced by CTIP2 and SUV39H1

机译：p21WAF1基因启动子被CTIP2和SUV39H1表观遗传沉默

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摘要

Mainly regulated at the transcriptional level, the cellular cyclin-dependent kinase inhibitor, CDKN1A/p21WAF1 (p21), is a major cell cycle regulator of the response to DNA damage, senescence and tumor suppression. Here, we report that COUP-TF-interacting protein 2 (CTIP2), recruited to the p21 gene promoter, silenced p21 gene transcription through interactions with histone deacetylases and methyltransferases. Importantly, treatment with the specific SUV39H1 inhibitor, chaetocin, repressed histone H3 lysine 9 trimethylation at the p21 gene promoter, stimulated p21 gene expression and induced cell cycle arrest. In addition, CTIP2 and SUV39H1 were recruited to the silenced p21 gene promoter to cooperatively inhibit p21 gene transcription. Induction of p21WAF1 gene upon human immunodeficiency virus 1 (HIV-1) infection benefits viral expression in macrophages. Here, we report that CTIP2 further abolishes Vpr-mediated stimulation of p21, thereby indirectly contributing to HIV-1 latency. Altogether, our results suggest that CTIP2 is a constitutive p21 gene suppressor that cooperates with SUV39H1 and histone methylation to silence the p21 gene transcription.
机译：细胞周期蛋白依赖性激酶抑制剂CDKN1A / p21WAF1（p21）主要在转录水平受到调控，是对DNA损伤，衰老和肿瘤抑制反应的主要细胞周期调节剂。在这里，我们报道，招募到p21基因启动子的COUP-TF相互作用蛋白2（CTIP2）通过与组蛋白脱乙酰基酶和甲基转移酶的相互作用沉默了p21基因的转录。重要的是，使用特定的SUV39H1抑制剂Chaetocin处理可抑制p21基因启动子处的组蛋白H3赖氨酸9三甲基化，刺激p21基因表达并诱导细胞周期停滞。此外，CTIP2和SUV39H1被募集到沉默的p21基因启动子上，以协同抑制p21基因的转录。在人类免疫缺陷病毒1（HIV-1）感染后诱导p21WAF1基因有助于巨噬细胞中的病毒表达。在这里，我们报道CTIP2进一步消除了Vpr介导的对p21的刺激，从而间接导致了HIV-1潜伏期。总而言之，我们的结果表明CTIP2是与SUV39H1和组蛋白甲基化协同作用以沉默p21基因转录的p21基因组成型抑制剂。

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