Journal article

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

Nobuhiro Okada, Chao-Po Lin, Marcelo C Ribeiro, Anne Biton, Gregory Lai, Xingyue He, Pengcheng Bu, Hannes Vogel, David M Jablons, Andreas C Keller, J Erby Wilkinson, Biao He, Terry P Speed, Lin He

GENES & DEVELOPMENT | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2014

Abstract

As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, sug..

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University of Melbourne Researchers

Grants

Awarded by National Cancer Institute (NCI)


Awarded by American Cancer Society (ACS)


Awarded by Tobacco-Related Disease Research Program (TRDRP)


Awarded by NATIONAL CANCER INSTITUTE


Funding Acknowledgements

We thank members of the He laboratory for their help and input. Particularly, we thank S. Nishimura, M.R. Junttila, M. McMahon, M. Winslow, M.J. Bennett, J. Shue, S.K. Greaney, K. Hou, D. Yang, and Y.J. Choi for technical assistance and stimulating discussions. We also thank P. Margolis helpful advice on manuscript preparation. We thank B. Zaghi and J. Ong for the technical assistance. L.H. is a Searle Scholar supported by the Kinship Foundation. L.H. also acknowledges the support of an R01 and an R21 grant from the National Cancer Institute (NCI; R01 CA139067 and 1R21CA175560-01), a research scholar award from American Cancer Society (ACS; 123339-RSG-12-265-01-RMC), and a research grant from The Tobacco-Related Disease Research Program (TRDRP; 21RT-0133). C.-P.L. is supported by a post-doctoral fellowship from the California Institute for Regenerative Medicine (CIRM) and a post-doctoral fellowship from the Siebel Foundation.