Journal article

DNA repair processes are critical mediators of p53-dependent tumor suppression

Ana Janic, Liz J Valente, Matthew J Wakefield, Leon Di Stefano, Liz Milla, Stephen Wilcox, Haoyu Yang, Lin Tai, Cassandra J Vandenberg, Andrew J Kueh, Shinsuke Mizutani, Margs S Brennan, Robyn L Schenk, Lisa M Lindqvist, Anthony T Papenfuss, Liam O'Connor, Andreas Strasser, Marco J Herold

NATURE MEDICINE | NATURE PUBLISHING GROUP | Published : 2018

Abstract

It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function3-5. To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1, promoted lymphoma/leukemia development only when PUMA and p21, the critical effectors of p53-driven..

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Grants

Awarded by Cancer Australia and Cure Cancer Australia Foundation


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by NHMRC Senior Principal Research Fellow (SPRF)


Awarded by Leukemia & Lymphoma Society of America (Specialized Center of Research (SCOR))


Funding Acknowledgements

We thank S. Lowe, A. Lujambio, A. Ventura and C. Concepcion for the p53 target gene shRNA library and for discussions; M. Ritchie, W. Shi, Y. Liao for data analysis, J.M. Adams, P. Bouillet, S. Cory, K. Rajewsky and A. Villunger for gifts of mice and for discussions. This work was supported by postdoctoral fellowships from the Leukemia & Lymphoma Society of America, Marie Curie Actions and Beatriu de Pinos, and Lady Tata Memorial Trust to A.J. and by grants from Cancer Australia and Cure Cancer Australia Foundation (grant no. 1067571), the National Health and Medical Research Council (NHMRC; program grant no. 1016701, NHMRC Senior Principal Research Fellow (SPRF) Fellowship 1020363 to A. S.), and the Leukemia & Lymphoma Society of America (Specialized Center of Research (SCOR) grant no. 7001-13), Australian Phenomics Network and a CCV Venture Grant. This work was made possible by operational infrastructure grants through the Australian Government Independent Medical Research Institutes Infrastructure Support Scheme (IRIISS) and the Victorian State Government Operational Infrastructure Support (OIS).