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

作者：Canne Ian G; Merrick Karl A; Morandell Sandra; Zhu Chang Qi; Braun Christian J; Grant Robert A; Cameron Eleanor R; Tsao Ming Sound; Hemann Michael T; Yaffe Michael B^*

来源：Cancer Cell, 2015, 28(5): 623-637.

DOI：10.1016/j.ccell.2015.09.009

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.

• 出版日期2015-11-9
• 单位MIT