Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters.
Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters.
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DOI：
10.1093/nar/gku501
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发表时间：
2014-07
影响因子：
14.9
通讯作者：
Meek DW
中科院分区：
文献类型：
--
作者：
Loughery J;Cox M;Smith LM;Meek DW
P53肿瘤抑制因子受各种应激刺激诱导，协调适应性基因表达程序，导致生长停滞或细胞死亡。一些刺激，如DNA损伤，导致快速和实质性的P53多位点磷酸化，最初通过丝氨酸15的磷酸化而成核。其他刺激，如过度增殖，不能刺激P53的磷酸化，这引发了关于磷酸化的生理作用的问题。在这里，我们表明，在未经刺激的细胞和药物刺激的细胞中都发生了基础水平的Ser15磷酸化，以诱导P53。用丙氨酸(S15A)替代Ser15的P53不能介导P53依赖的转录或生长停滞，但可以用天冬氨酸(S15D：一种磷酸化模拟物)替代来挽救。染色质免疫沉淀(ChIP)分析表明，虽然wt-和S15A-P53可在CDKN1A(P21)启动子上检测到(作为具有代表性的P53响应启动子)，但S15A-P53不刺激组蛋白乙酰化(染色质松弛的衡量标准)，也不刺激其募集，以响应DNA损伤或药物刺激。这些数据表明，在P53反应启动子的生理背景下，Ser15的磷酸化是P53功能所必需的，并表明即使是低水平的这种修饰在促进P53转录功能方面也具有关键的和可能的普遍作用。
The p53 tumour suppressor is induced by various stress stimuli and coordinates an adaptive gene expression programme leading to growth arrest or cell death. Some stimuli, such as DNA damage, lead to rapid and substantial multisite phosphorylation of p53, nucleated initially through phosphorylation of serine 15. Other stimuli, such as hyper-proliferation, do not stimulate p53-phosphorylation, raising questions regarding the physiological role for phosphorylation. Here, we show that a basal level of Ser15 phosphorylation occurs in both unstimulated cells and cells stimulated pharmacologically to induce p53. p53 in which Ser15 is substituted by alanine (S15A) fails to mediate p53-dependent transcription or growth arrest but can be rescued by substitution with aspartate (S15D: a phospho-mimic). Chromatin immunoprecipitation (ChIP) analyses show that, while wt- and S15A-p53 are detectable on the CDKN1A (p21) promoter (as a representative p53-responsive promoter), S15A-p53 does not stimulate histone acetylation (a measure of chromatin relaxation), nor is its recruitment stimulated, in response to a DNA damage or pharmacological stimulus. These data demonstrate that Ser15 phosphorylation is required for p53 function in the physiological context of p53-responsive promoters and suggest a key and possibly universal role even for low levels of this modification in promoting p53-transcription function.
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