How phosphorylation controls p53
How phosphorylation controls p53
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DOI：
10.4161/cc.10.6.15076
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发表时间：
2011-03-15
期刊：
影响因子：
4.3
通讯作者：
Hupp, Ted R.
中科院分区：
文献类型：
--
作者：
MacLaine, Nicola J.;Hupp, Ted R.
肿瘤抑制因子p53是一种转录因子，它将不同的环境信号（包括DNA损伤、代谢应激、癌基因激活、缺氧和病毒感染）整合成一个共同的生物学结果，维持正常的细胞控制和组织完整性。P53在翻译后水平受到蛋白-蛋白相互作用和共价修饰的调控，包括超过20个磷酸化受体位点的磷酸化。从这个角度来看，我们讨论了两个进化上保守的p53磷酸化基序的功能，它们位于n端反激活和c端调节结构域，最近被证明在干细胞小生境中发挥肿瘤抑制作用。我们还考虑了应激激活激酶磷酸化之外的机制如何导致p53作为转录因子的激活，我们回顾了p53激活激酶作为肿瘤抑制因子和癌蛋白的双重作用。最后，我们讨论了p53特异性活性的变化如何不仅对癌症发展而且对生物体衰老产生深远影响。
The tumor suppressor p53 is a transcription factor that integrates distinct environmental signals including DNA damage, metabolic stress, oncogene activation, hypoxia and virus infection into a common biological outcome that maintains normal cellular control and tissue integrity. p53 is regulated at the post-translational level by protein-protein interactions and covalent modifications, including phosphorylation at over twenty phosphor-acceptor sites. In this perspective we discuss the function of two evolutionarily conserved p53 phosphorylation motifs, located within the N-terminal transactivation and C-terminal regulatory domains, which have recently been shown to play a tumor suppressive role in stem cell niches. We also consider how mechanisms in addition to phosphorylation by stress-activated kinases can lead to the activation of p53 as a transcription factor, and we review the dual role of p53-activating kinases as tumor suppressors and oncoproteins. Finally, we discuss how changes in the specific activity of p53 can have profound effects not only on cancer development but also on organism aging.