title: A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression.
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, 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.
authors.affiliation: Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA;
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Okada
authors.forename: Chao-Po
authors.initials: CP
authors.lastname: Lin
authors.forename: Marcelo C
authors.initials: MC
authors.lastname: Ribeiro
authors.forename: Anne
authors.initials: A
authors.lastname: Biton
authors.forename: Gregory
authors.initials: G
authors.lastname: Lai
authors.forename: Xingyue
authors.initials: X
authors.lastname: He
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Bu
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Keller
authors.forename: J Erby
authors.initials: JE
authors.lastname: Wilkinson
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.forename: Terry P
authors.initials: TP
authors.lastname: Speed
authors.forename: Lin
authors.initials: L
authors.lastname: He
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D057895:Haploinsufficiency; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins
keywords: HDM4; Mdm4; miR-34; microRNAs; p53