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Cancer Cell. 2015 Nov 9;28(5):623-637. 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.

Author information

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.
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Contributed equally

Erratum in

  • Cancer Cell. 2015 Dec 14;28(6):831.

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.

PMID:
26602816
PMCID:
PMC4830093
DOI:
10.1016/j.ccell.2015.09.009
[Indexed for MEDLINE]
Free PMC Article

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