Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding.
Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding.
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突变体 p53 通过 CDK4 丝氨酸 249 磷酸化后的 c-Myc 激活以及随后的 PIN1 结合获得其功能
DOI：
10.1016/j.molcel.2017.11.006
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发表时间：
2017-12-21
期刊：
影响因子：
16
通讯作者：
Lu H
中科院分区：
文献类型：
--
作者：
Liao P;Zeng SX;Zhou X;Chen T;Zhou F;Cao B;Jung JH;Del Sal G;Luo S;Lu H
TP53错义突变通过不同机制获得新功能（GOF），显著影响各种人类癌症的发生和进展。在这里，我们报告了p53- r249s （p53- rs）的GOF的独特机制，p53- rs是人类肝细胞癌（HCC）中经常检测到的p53突变体，与乙型肝炎感染和黄曲霉毒素B1高度相关。CDK抑制剂阻断p53-RS在HCC中的核易位，而CDK4在细胞G1/S期与p53-RS相互作用，使其磷酸化，并增强其核定位。这与肽基脯氨酸顺式反式异构酶1 （NIMA-interacting 1, PIN1）与p53- rs结合结合，但不是p53形式，先前显示的4丝氨酸突变对PIN1的结合至关重要。因此，p53-RS与c-Myc相互作用，增强了c-Myc依赖性rDNA转录关键的核糖体生物发生。这些结果揭示了CDK4-PIN1-p53-RS-c-Myc通路作为HCC中p53-RS的GOF的新机制。Liao等的研究揭示了一种独特的分子通路，在HBV和黄曲霉毒素b1相关的人类肝癌中，肿瘤抑制因子p53在一个热点位点选择性突变，使突变的p53在促进肝癌细胞生长方面更具致癌作用。
TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS’s nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization. This is coupled with binding of a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) to p53-RS, but not the p53 form with mutations of 4 serines previously shown to be crucial for PIN1-binding. As a result, p53-RS interacts with c-Myc and enhances c-Myc-dependent rDNA transcription key for ribosomal biogenesis. These results unveil a CDK4-PIN1-p53-RS-c-Myc pathway as a novel mechanism for the GOF of p53-RS in HCC. The study by Liao et al unveils a unique molecular pathway that conveys selective mutation of the tumor suppressor p53 at a hot spot site solely found in HBV- and aflatoxin B1-associated human liver cancers and renders the mutated p53 more oncogenic in promoting liver cancer cell growth.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
5.3
作者：
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影响因子：
64.8
作者：
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通讯作者：
OZTURK, M
影响因子：
11.2
作者：
Jung, Jin Kyu;Arora, Payal;Jang, Kyung Lib
通讯作者：
Jang, Kyung Lib
影响因子：
64.5
作者：
CHISARI, FV;KLOPCHIN, K;PALMITER, RD
通讯作者：
PALMITER, RD