A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy

被引：66

作者：

Canne, Ian G. ^{[1
]}

Merrick, Karl A. ^{[1
]}

Morandell, Sandra ^{[1
]}

Zhu, Chang-Qi ^{[2
,3
]}

Braun, Christian J. ^{[1
]}

Grant, Robert A. ^{[1
]}

Cameron, Eleanor R. ^{[1
]}

Tsao, Ming-Sound ^{[2
,3
]}

Hemann, Michael T. ^{[1
]}

Yaffe, Michael B. ^{[1
,4
,5
,6
]}

机构：

[1] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[2] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada

[3] Univ Toronto, Toronto, ON M5G 2M9, Canada

[4] MIT, Dept Biol, Cambridge, MA 02139 USA

[5] MIT, Dept Biol Engn, Cambridge, MA 02139 USA

[6] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg, Boston, MA 02215 USA

来源：

CANCER CELL | 2015年 / 28卷 / 05期

基金：

奥地利科学基金会;

关键词：

DNA-DAMAGE RESPONSE; ADJUVANT CHEMOTHERAPY; MESSENGER-RNAS; P53; PHOSPHORYLATION; IDENTIFICATION; INHIBITOR; P27(KIP1); NETWORK; ATM;

D O I：

10.1016/j.ccell.2015.09.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

In normal cells, p53 is activated by DNA damage checkpoint kinases to simultaneously control the G1/S and G2/M cell cycle checkpoints through transcriptional induction of p21(cip1) and Gadd45 alpha. In p53-mutant tumors, cell cycle checkpoints are rewired, leading to dependency on the p38/MK2 pathway to survive DNA-damaging chemotherapy. Here we show that the RNA binding protein hnRNPA0 is the "successor" to p53 for checkpoint control. Like p53, hnRNPA0 is activated by a checkpoint kinase (MK2) and simultaneously controls both cell cycle checkpoints through distinct target mRNAs, but unlike p53, this is through the post-transcriptional stabilization of p27(Kip1) and Gadd45 alpha mRNAs. This pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control to chemotherapy response.

引用

页码：623 / 637

页数：15

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