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

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, possi...

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Published in:	Genes & development Vol. 28; no. 5; pp. 438 - 450
Main Authors:	Okada, Nobuhiro, Lin, Chao-Po, Ribeiro, Marcelo C, Biton, Anne, Lai, Gregory, He, Xingyue, Bu, Pengcheng, Vogel, Hannes, Jablons, David M, Keller, Andreas C, Wilkinson, J Erby, He, Biao, Speed, Terry P, He, Lin
Format:	Journal Article
Language:	English
Published:	United States Cold Spring Harbor Laboratory Press 01-03-2014
Subjects:	Adenocarcinoma - physiopathology Adenocarcinoma of Lung Animals Cell Line, Tumor Feedback, Physiological Gene Deletion Gene Expression Regulation, Neoplastic Haploinsufficiency Humans Lung Neoplasms - physiopathology Mice MicroRNAs - genetics MicroRNAs - metabolism Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism ras Proteins - genetics ras Proteins - metabolism Research Paper Tumor Cells, Cultured Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism microRNAs HDM4 Mdm4 miR-34 p53
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Summary:	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, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 3' untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0890-9369 1549-5477
DOI:	10.1101/gad.233585.113