Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression.
Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression.
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DOI：
10.1101/gad.301564.117
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发表时间：
2017-08-15
影响因子：
10.5
通讯作者：
Hu W
中科院分区：
文献类型：
--
作者：
Yue X;Zhang C;Zhao Y;Liu J;Lin AW;Tan VM;Drake JM;Liu L;Boateng MN;Li J;Feng Z;Hu W
在这里，岳等人。研究了p53功能获得性（GOF）突变的机制，发现突变型p53激活小GTPase Rac1是突变型p53 GOF促进肿瘤进展的关键机制。他们的研究结果提供了对肿瘤中 Rac1 激活的新机制的深入了解，并表明 Rac1 的激活是突变 p53 GOF 在肿瘤发生中的一个未识别的关键机制。肿瘤抑制因子 p53 在人类癌症中经常发生突变。突变的 p53 通常通过功能获得 (GOF) 机制促进肿瘤进展。然而，突变型 p53 GOF 的机制尚不清楚。在这项研究中，我们发现突变型p53激活小GTPase Rac1是突变型p53 GOF促进肿瘤进展的关键机制。从机制上讲，突变型 p53 与 Rac1 相互作用，并抑制其与 SUMO 特异性蛋白酶 1 (SENP1) 的相互作用，进而抑制 SENP1 介导的 Rac1 去 SUMO 化，从而激活 Rac1。通过 RNAi 靶向 Rac1 信号传导、显性失活 Rac1 (Rac1 DN) 的表达或特异性 Rac1 抑制剂 NSC23766 可以极大地抑制突变型 p53 GOF 促进肿瘤生长和转移。此外，突变型 p53 表达与临床肿瘤样本中 Rac1 活性增强相关。这些结果揭示了肿瘤中 Rac1 激活的新机制，最重要的是，揭示了 Rac1 激活是突变 p53 GOF 在肿瘤发生中的一个未识别的关键机制，可以作为含有突变 p53 的肿瘤的治疗靶点。
Here, Yue et al. investigated the mechanisms underlying p53 gain-of-function (GOF) mutations and found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Their findings provide insight into a new mechanism for Rac1 activation in tumors and show that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis. Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.
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影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
5.7
作者：
Bid HK;Roberts RD;Manchanda PK;Houghton PJ
通讯作者：
Houghton PJ
影响因子：
3
作者：
Duan, Wenrui;Gao, Li;Villalona-Calero, Miguel A.
通讯作者：
Villalona-Calero, Miguel A.
影响因子：
64.8
作者：
Alexandrova EM;Yallowitz AR;Li D;Xu S;Schulz R;Proia DA;Lozano G;Dobbelstein M;Moll UM
通讯作者：
Moll UM
影响因子：
12.4
作者：
Liu, Ju;Zhang, C.;Feng, Z.
通讯作者：
Feng, Z.