A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Okada, N., Lin, C., Ribeiro, M. C, Biton, A., Lai, G., He, X., Bu, P., Vogel, H., Jablons, D. M, Keller, A. C, Wilkinson, J E., He, B., Speed, T. P, & He, L. Genes & development, 28:438–450, March, 2014.
doi  abstract   bibtex   
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.
@Article{Okada2014,
  author          = {Okada, Nobuhiro and Lin, Chao-Po and Ribeiro, Marcelo C and Biton, Anne and Lai, Gregory and He, Xingyue and Bu, Pengcheng and Vogel, Hannes and Jablons, David M and Keller, Andreas C and Wilkinson, J Erby and He, Biao and Speed, Terry P and He, Lin},
  title           = {A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression.},
  journal         = {Genes \& development},
  year            = {2014},
  volume          = {28},
  pages           = {438--450},
  month           = mar,
  issn            = {1549-5477},
  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. },
  chemicals       = {MIRN34 microRNA, human, MIRN34 microRNA, mouse, MicroRNAs, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, ras Proteins},
  citation-subset = {IM},
  completed       = {2014-04-21},
  country         = {United States},
  doi             = {10.1101/gad.233585.113},
  issn-linking    = {0890-9369},
  issue           = {5},
  keywords        = {Adenocarcinoma, physiopathology; Animals; Cell Line, Tumor; Feedback, Physiological; Gene Deletion; Gene Expression Regulation, Neoplastic; Haploinsufficiency; Humans; Lung Neoplasms, physiopathology; Mice; MicroRNAs, genetics, metabolism; Proto-Oncogene Proteins, genetics, metabolism; Tumor Cells, Cultured; Tumor Suppressor Protein p53, genetics, metabolism; ras Proteins, genetics, metabolism; HDM4; Mdm4; miR-34; microRNAs; p53},
  nlm-id          = {8711660},
  owner           = {NLM},
  pii             = {gad.233585.113},
  pmc             = {PMC3950342},
  pmid            = {24532687},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2016-10-19},
}
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