Title | A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Cannell, IG, Merrick, KA, Morandell, S, Zhu, C-Q, Braun, CJ, Grant, RA, Cameron, ER, Tsao, M-S, Hemann, MT, Yaffe, MB |
Journal | Cancer Cell |
Volume | 28 |
Issue | 5 |
Pagination | 623-37 |
Date Published | 2015 Nov 9 |
ISSN | 1878-3686 |
Keywords | Aged, Animals, Antineoplastic Agents, Cell Cycle Checkpoints, Cell Cycle Proteins, Cell Line, Tumor, Cisplatin, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Genetic Pleiotropy, HEK293 Cells, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Male, Mice, Inbred C57BL, Middle Aged, Mutation, Neoplasms, Nuclear Proteins, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Survival Analysis, Tumor Suppressor Protein p53 |
Abstract | 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 Gadd45α. 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 Gadd45α mRNAs. This pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control to chemotherapy response. |
DOI | 10.1016/j.ccell.2015.09.009 |
Alternate Journal | Cancer Cell |
PubMed ID | 26602816 |
PubMed Central ID | PMC4830093 |
Grant List | CA112967 / CA / NCI NIH HHS / United States ES-002109 / ES / NIEHS NIH HHS / United States ES015339 / ES / NIEHS NIH HHS / United States GM59281 / GM / NIGMS NIH HHS / United States GM60594 / GM / NIGMS NIH HHS / United States P30-CA14051 / CA / NCI NIH HHS / United States R01 ES015339 / ES / NIEHS NIH HHS / United States R01 GM104047 / GM / NIGMS NIH HHS / United States U54 CA112967 / CA / NCI NIH HHS / United States |