The gain of function of p53 mutant p53S in promoting tumorigenesis by cross-talking with H-RasV12.
The gain of function of p53 mutant p53S in promoting tumorigenesis by cross-talking with H-RasV12.
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p53 突变体 p53S 通过与 H-RasV12 相互作用获得促进肿瘤发生的功能
DOI：
10.7150/ijbs.4176
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发表时间：
2012
影响因子：
9.2
通讯作者：
Luo Y
中科院分区：
文献类型：
--
作者：
Jia S;Zhao L;Tang W;Luo Y
野生型p53肿瘤抑制功能的丧失和p53突变体的致癌性功能获得在肿瘤发生中显示出重要意义。p53 N236 S（人类p53 N239 S，p53 S）突变已被酵母试验证明失去野生型p53功能。然而，其功能增益尚不清楚。通过凝胶迁移实验，我们发现突变型p53 S已经失去了与其靶启动子的DNA结合能力。进一步的实时荧光定量PCR结果证实，p53 S在10 Gy照射后已丧失了调控p21 Cip 1/Waf 1、cyclin G、p53 A和Bax转录的功能。这些数据证实了哺乳动物细胞中p53 S功能的丧失。通过异种移植实验，我们发现p53 S本身并不足以致瘤，但是，p53 S与H-RasV 12协同作用可以显著促进p53缺失的MEFs的成瘤。进一步研究表明，p53 S和H-RasV 12共表达可提高H-RasV 12的表达水平，并部分消除p53 S和H-RasV 12引起的Chk 2、γ-H2 AX、Hsp 70、Rb、p16 Ink 4a等应激反应蛋白的升高。提示p53 S与H-RasV 12发生交叉作用，降低细胞对致癌信号的应激反应，促进细胞生长和肿瘤发生。这些数据为p53 S和H-RasV 12的协同作用提供了分子基础，并揭示了p53 S在与H-RasV 12的交叉对话中的功能增益。本研究揭示了p53突变体功能获得的一个重要方面，因此可能为靶向p53突变体的临床策略提供启示。
The loss of wild type p53 tumor suppressive function and oncogenic gain-of-function of p53 mutants have been showing important implications in tumorigenesis. The p53N236S (p53N239S in human, p53S) mutation has been shown to lose wild type p53 function by yeast assay. However, its gain of function is still not clear. By gel shift assay, we showed that mutant p53S had lost its DNA binding ability to its target promoters. Further real-time PCR data confirmed that p53S had lost the function of regulating the transcription of p21 Cip1/Waf1, cyclin G, PUMA, and Bax in response to 10Gy irradiation. These data confirmed the loss of function of p53S in mammalian cells. By xenograft assay, we showed that the p53S per se was not oncogenic enough to form tumor, however, cooperating with H-RasV12, p53S could dramatically promote tumorigenesis in p53 null MEFs. Further study showed that co-expression of p53S and H-RasV12 could increase the expression level of H-RasV12 and partially eliminate the elevation of stress response proteins such as Chk2, γ-H2AX, Hsp70, Rb, p16Ink4a caused by either p53S or H-RasV12. These data suggested that p53S cross-talked with H-RasV12 and reduced the cellular stress response to oncogenic signals, which facilitated the cell growth and tumorigenesis. Together these data provided the molecular basis for the cooperation of p53S and H-RasV12 and revealed the gain of function of p53S in cross-talking with H-RasV12. This study revealed an important aspect of gain of function for p53 mutant, therefore might shed light on the clinical strategy in targeting p53 mutant.
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影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
3.9
作者：
Petitjean, Audrey;Mathe, Ewy;Olivier, Magali
通讯作者：
Olivier, Magali
影响因子：
11.4
作者：
Brachmann, RK;Yu, KX;Boeke, JD
通讯作者：
Boeke, JD
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
5.3
作者：
Martínez-Gac, L;Marqués, M;Carrera, AC
通讯作者：
Carrera, AC