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

Research output: Contribution to journalArticle

154 Citations (Scopus)

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 39 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.

Original languageEnglish
Pages (from-to)438-450
Number of pages13
JournalGenes and Development
Volume28
Issue number5
DOIs
Publication statusPublished - Mar 1 2014

Keywords

  • HDM4
  • Mdm4
  • MicroRNAs
  • miR-34
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Okada, N., Lin, C. P., Ribeiro, M. C., Biton, A., Lai, G., He, X., Bu, P., Vogel, H., Jablons, D. M., Keller, A. C., Erby Wilkinson, J., He, B., Speed, T. P., & He, L. (2014). A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes and Development, 28(5), 438-450. https://doi.org/10.1101/gad.233585.113