A positive feedback between p53 and
                    <i>miR-34</i>
                    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

doi:10.1101/gad.233585.113

<jats:p> As bona fide p53 transcriptional targets, <jats:italic>miR-34</jats:italic> microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, <jats:italic>miR-34</jats:italic> 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 <jats:italic>miR-34a</jats:italic> represses <jats:italic>HDM4</jats:italic> , a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a <jats:italic>Kras</jats:italic> -induced mouse lung cancer model, <jats:italic>miR-34a</jats:italic> deficiency alone does not exhibit a strong oncogenic effect. However, <jats:italic>miR-34a</jats:italic> deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53– <jats:italic>miR-34</jats:italic> feedback loop can enhance oncogenesis in a specific context. The importance of the p53/ <jats:italic>miR-34</jats:italic> /HDM4 feedback loop is further confirmed by an inverse correlation between <jats:italic>miR-34</jats:italic> and full-length <jats:italic>HDM4</jats:italic> in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short <jats:italic>HDM4</jats:italic> isoform through alternative polyadenylation. This short <jats:italic>HDM4</jats:italic> isoform lacks <jats:italic>miR-34</jats:italic> -binding sites in the 3′ untranslated region (UTR), thereby evading <jats:italic>miR-34</jats:italic> regulation to disable the p53- <jats:italic>miR-34</jats:italic> positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and <jats:italic>miR-34</jats:italic> miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop. </jats:p>

A positive feedback between p53 and <i>miR-34</i> miRNAs mediates tumor suppression

書誌事項

この論文をさがす

説明

収録刊行物

被引用文献 (5)*注記

キーワード

詳細情報詳細情報について

書き出し

問題の指摘