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

描述（申请人提供）：p53是最常突变的肿瘤抑制因子，被认为是基因组的守护者。过去三十年的深入研究已经将p53置于一个复杂分子网络的中心，该网络调节对癌症相关应激信号的多种生理反应。在以前的研究中，p53网络的组成部分仅由蛋白质编码基因组成，包括上游作用于调节p53活性的基因，下游作用于介导p53效应的基因，以及形成调节p53活性动力学的调节反馈环的基因。我们小组和其他人最近的研究已经确定了一个家族的microRNAs（miRNAs），mir-34 a，B和c，作为p53真正的转录靶点。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是一类新型的小的、调节性的非编码RNA，其介导大量靶mRNA的转录后基因沉默。mir-34 miRNAs的异位表达模拟了p53在生长停滞和凋亡中的生物学作用，可能是通过它们抑制促增殖和促存活基因表达的能力。鉴于这些初步发现，我们假设内源性mir-34 miRNAs是介导许多p53下游效应的关键效应子，并且mir-34的功能对肿瘤发生和肿瘤维持具有深远影响。利用细胞培养研究和小鼠遗传学研究，我们建议确定mir-34 miRNAs是否介导p53诱导的生长停滞和凋亡，以及mir-34 miRNAs在多大程度上有助于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.