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

Okada, N; Lin, CP; Ribeiro, MC; Biton, A; Lai, G; He, X; Bu, P; Vogel, H; Jablons, DM; Keller, AC; Wilkinson, JE; He, B; Speed, TP; He, L

Author(s): Okada, N; Lin, CP; Ribeiro, MC; Biton, A; Lai, G; He, X; Bu, P; Vogel, H; Jablons, DM; Keller, AC; Wilkinson, JE; He, B; Speed, TP; He, L;
Details: Publication Year 2014-03-01,Volume 28,Issue #5,Page 438-50
Journal Title: Genes & Development
Publication Type: Journal Article
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.
Publisher: CSH
Research Division(s): Bioinformatics
Publisher's Version: https://doi.org/10.1101/gad.233585.113
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2014-07-10 09:26:33