The histone acetyltransferase PCAF regulates p21 transcription through stress-induced acetylation of histone H3
The histone acetyltransferase PCAF regulates p21 transcription through stress-induced acetylation of histone H3
复制标题
DOI：
10.4161/cc.20864
复制
发表时间：
2012-07-01
期刊：
影响因子：
4.3
通讯作者：
Androphy, Elliot J.
中科院分区：
文献类型：
--
作者：
Love, Ian M.;Sekaric, Pedja;Androphy, Elliot J.
P53作为一种肿瘤抑制因子的活性主要取决于它在应对遗传毒性和其他潜在的突变压力时反式激活特定靶基因的能力。几种组蛋白乙酰转移酶(HATS)，包括p300、CBP、PCAF和GCN5，参与了细胞周期蛋白依赖性激酶(CDK)抑制物p21和其他靶基因的P53依赖转录的激活。在这里，我们表明，PCAF，而不是CBP或p300，是P53依赖的p21表达的关键调节因子，以响应多个P53激活压力。PCAF是PCAF在P53缺失细胞、Nutlin-3、DNA损伤剂和p14(ARF)表达中响应外源性P53转录激活p21所必需的，这表明PCAF在应激后P53信号转导p21中具有广泛的需求。重要的是，缺乏PCAF的细胞不能响应Nutlin-3的处理或p14(ARF)的表达而经历细胞周期停滞，这与PCAF在这一p53功能中的生理作用是一致的。令人惊讶的是，PCAF在诱导p21中的作用不依赖于PCAF介导的乙酰化靶点p53赖氨酸320乙酰化。尽管p21启动子被PCAF基因敲除并未改变，但p21转录的激活需要完整的PCAF HAT结构域，并且P53对p21启动子上染色质标记乙酰基-H3K9和乙酰基-H3K14的诱导依赖于PCAF的生理水平。总之，我们的实验表明，PCAF是p21启动子上应激反应的组蛋白3乙酰化、P53指导的p21转录以及由此导致的生长停滞所必需的。
The activity of p53 as a tumor suppressor primarily depends on its ability to transactivate specific target genes in response to genotoxic and other potentially mutagenic stresses. Several histone acetyl transferases (HATs), including p300, CBP, PCAF and GCN5 have been implicated in the activation of p53-dependent transcription of the cyclin-dependent kinase (cdk) inhibitor p21 as well as other target genes. Here we show that PCAF, but not CBP or p300, is a critical regulator of p53-dependent p21 expression in response to multiple p53-activating stresses. PCAF was required for the transcriptional activation of p21 in response to exogenous p53 in p53-null cells, Nutlin-3, DNA damaging agents and p14(ARF) expression, suggesting a broad requirement for PCAF in p53 signaling to p21 after stress. Importantly, cells lacking PCAF failed to undergo cell cycle arrest in response to Nutlin-3 treatment or p14(ARF) expression, consistent with a physiologically important role for PCAF in this p53 function. Surprisingly, the role for PCAF in induction of p21 was independent of p53 lysine 320 acetylation, a previously suggested target of PCAF-mediated acetylation. Though p21 promoter occupancy by p53 was not altered by PCAF knockdown, activation of p21 transcription required an intact PCAF HAT domain, and induction of chromatin marks acetyl-H3K9 and acetyl-H3K14 at the p21 promoter by p53 was dependent upon physiologic levels of PCAF. Together, our experiments indicate that PCAF is required for stress-responsive histone 3 acetylation at the p21 promoter, p53-directed transcription of p21 and the resultant growth arrest.