A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy
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Yaffe_A Pleiotropic Rna.pdf
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2.78 MB
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Author(s)
Grant, Robert A.
Tsao, Ming-Sound
Cannell, Ian Gordon
Merrick, Karl Andrew
Morandell, Sandra M.
Grant, Robert A
Cameron, Eleanor Ruth
Hemann, Michael
Yaffe, Michael B
Braun, Christian Joerg
Date Issued
October 2014
Journal
Cancer Cell
Publisher
Elsevier
Citation
Cannell, Ian G. et al. “A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy.” Cancer Cell 28.5 (2015): 623–637.
Version
Author's final manuscript
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[superscript 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[superscript Kip1] and Gadd45α mRNAs. This pathway drives cisplatin resistance in lung cancer demonstrating the importance of post-transcriptional RNA control to chemotherapy response.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.ccell.2015.09.009
