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

Ian G Cannell; Karl A Merrick; Sandra Morandell; Chang-Qi Zhu; Christian J Braun; Robert A Grant; Eleanor R Cameron; Ming-Sound Tsao; Michael T Hemann; Michael B Yaffe

doi:10.1016/j.ccell.2015.09.009

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

Cancer Cell. 2015 Nov 9;28(5):623-637. doi: 10.1016/j.ccell.2015.09.009.

Authors

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Princess Margaret Cancer Centre, University Health Network and University of Toronto, Canada.
³ Department of Biology, Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Biological Engineering, Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 USA.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Antineoplastic Agents / therapeutic use
Cell Cycle Checkpoints / genetics*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cisplatin / therapeutic use
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Drug Resistance, Neoplasm / genetics*
Female
Gene Expression Regulation, Neoplastic
Genetic Pleiotropy
HEK293 Cells
Heterogeneous-Nuclear Ribonucleoproteins / genetics*
Heterogeneous-Nuclear Ribonucleoproteins / metabolism
Humans
Male
Mice, Inbred C57BL
Middle Aged
Mutation*
Neoplasms / drug therapy
Neoplasms / genetics*
Neoplasms / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Survival Analysis
Tumor Suppressor Protein p53 / genetics*

Substances

Antineoplastic Agents
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
GADD45A protein, human
HNRNPA0 protein, human
Heterogeneous-Nuclear Ribonucleoproteins
Nuclear Proteins
Tumor Suppressor Protein p53
Cyclin-Dependent Kinase Inhibitor p27
Cisplatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding