Functions of mir-34 microRNAs in the p53 tumor suppressor pathway

描述(申请人提供)：P53是最常发生突变的肿瘤抑制基因，被认为是基因组的守护者。在过去的三十年里，密集的研究已经将p53置于一个复杂的分子网络的中心，该网络调节着对癌症相关应激信号的不同生理反应。在以前的研究中，P53网络的组成部分只由蛋白质编码基因组成，包括上游调节P53活性的基因，下游调节P53活性的基因，以及形成调节P53活性动态的调控反馈环的基因。我们小组和其他人最近的研究发现，一个家族microRNAs(MiRNAs)mir-34a、b和c是p53的真正转录靶点。这些发现首次揭示了蛋白质和非编码RNA在这一最重要的肿瘤抑制途径中的相互作用。MiRNAs是一类新型的小分子非编码RNA，介导大量靶向mRNAs转录后基因沉默。Mir-34miRNAs的异位表达模拟了p53在生长停滞和凋亡中的生物学作用，可能是通过抑制促增殖和促生存基因的表达而实现的。根据这些初步发现，我们假设内源性mir-34miRNAs是介导许多p53下游效应的关键效应者，并且mir-34的功能对肿瘤的发生和维持具有深远的影响。通过细胞培养研究和小鼠遗传学研究，我们建议确定mir-34miRNAs是否介导了p53诱导的生长停滞和凋亡，以及mir-34miRNAs在多大程度上促进了p53介导的肿瘤抑制和肿瘤消退。

DESCRIPTION (provided by applicant): p53, the most frequently mutated tumor suppressor, is regarded as the guardian of the genome. Intensive studies over the past three decades have placed p53 in the center of a complex molecular network regulating diverse physiological responses to cancer- related stress signals. In previous studies, the components of the p53 network solely consist of protein coding genes, including those acting upstream to regulate p53 activity, those functioning downstream to mediate p53 effects, and those forming a regulatory feedback loop regulating the dynamics of the p53 activity. Recent studies from our group and others have identified a family microRNAs (miRNAs), mir-34a, b and c, as bona fide transcriptional targets of p53. These findings, for the first time, revealed the interplay between proteins and non-coding RNAs in this most important tumor suppressor pathway. miRNAs are a novel class of small, regulatory non-coding RNAs that mediate post-transcriptional gene silencing of a large number of target mRNAs. The ectopic expression of mir-34 miRNAs mimics the biological effects of p53 in growth arrest and apoptosis, possibly through their ability to dampen the expression of pro-proliferation and pro-survival genes. Given these preliminary findings, we hypothesize that the endogenous mir-34 miRNAs are key effectors to mediate many of the p53 downstream effects, and that the functions of mir-34 have profound impacts on tumorigenesis and tumor maintenance. Using cell culture studies and mouse genetic studies, we propose to determine whether mir-34 miRNAs mediate p53 induced growth arrest and apoptosis, and to what extent mir-34 miRNAs contribute to p53 mediated tumor suppression and tumor regression.