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The role of the p63-RBM38 loop in tumor suppression

p63-RBM38环在肿瘤抑制中的作用

基本信息

批准号：
9904126
负责人：
Xinbin Chen
金额：
$ 35.91万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904126
关键词：
3&apos Untranslated Regions Binding Biological Biological Process Biology Cell Aging Clinical Trials Development Ectopic Expression Elements Epidermis Epithelial Cells Family Genes Genetic Transcription Growth Health Human Knock-in Mouse Knock-out Knockout Mice Longevity Malignant Neoplasms MicroRNAs Mus N-terminal Oncoproteins Pathway interactions Pattern Phosphorylation Phosphotransferases Play Premature aging syndrome Protein Isoforms Protein p53 Proteins RNA Recognition Motif RNA-Binding Proteins Regulation Reverse Transcriptase Polymerase Chain Reaction Role Serine Spleen Stratified Epithelium TP53 gene Testing Thymus Gland Tissues Transcript Tumor Suppression Tumor Suppressor Proteins cell growth cell motility cell type differential expression inhibitor/antagonist insight mRNA Stability member mimetics mouse model overexpression premature promoter public health relevance tumor

项目摘要

p63 is a p53 family tumor suppressor. When p63 is expressed from the P1 promoter, five TAp63 isoforms (α, β, γ, δ, ε) are produced. When p63 is expressed from theP2 promoter, five ΔNp63 isoforms are produced. While the transcripts for ten p63 isoforms can be detected by RT-PCR, only proteins for p63α and p63γ are found to be detectable and thus the focus of the study. TAp63 contains an N- terminal activation domain conserved in p53 and regulates an array of genes for growth suppression. Indeed, mice deficient in TAp63 are prone to spontaneous tumors and premature aging. In contrast, ΔNp63, which contains a unique N-terminal activation domain, is required for proper development of epidermis and other stratified epithelial cells. Additionally, ΔNp63 is overexpressed in cancer and classified as an oncoprotein. Rbm38, also called RNPC1, is a RNA-binding protein with one RNA recognition motif (RRM) and a target of p63. Interestingly, we found that Rbm38 inhibits p63α mRNA stability via binding to p63 3' untranslated region (3'UTR). Thus, the mutual regulation between p63 and Rbm38 prompts us to hypothesize that the p63-Rbm38 loop plays a key role in p63-dependent tumor suppression and longevity. The hypothesis will be tested in the following three specific aims: (1) to determine how p63α and p63γ are differentially regulated by Rbm38; (2) to determine whether Rbm38 regulates TAp63- and p63γ-dependent premature aging and tumor suppression; (3) to determine how the p63-Rbm38 loop is regulated and its biological significance.

p63 是 p53 家族肿瘤抑制因子。当 p63 从 P1 启动子表达时，会产生五种 TAp63 同工型（α、β、γ、δ、ε）。当p63从P2启动子表达时，产生五种ΔNp63亚型。虽然 RT-PCR 可以检测到 10 种 p63 亚型的转录本，但仅发现 p63α 和 p63γ 的蛋白质可检测，因此是研究的重点。 TAp63 包含 p53 中保守的 N 端激活结构域，并调节一系列基因以抑制生长。事实上，缺乏 TAp63 的小鼠容易发生自发性肿瘤和过早衰老。相比之下，ΔNp63 含有独特的 N 末端激活结构域，是表皮和其他分层上皮细胞正常发育所必需的。此外，ΔNp63 在癌症中过度表达，被归类为癌蛋白。 Rbm38，也称为 RNPC1，是一种 RNA 结合蛋白，具有一个 RNA 识别基序 (RRM) 和 p63 的靶标。有趣的是，我们发现 Rbm38 通过与 p63 3' 非翻译区 (3'UTR) 结合来抑制 p63α mRNA 稳定性。因此，p63 和 Rbm38 之间的相互调节促使我们假设 p63-Rbm38 环在 p63 依赖性肿瘤抑制和长寿中发挥关键作用。该假设将在以下三个具体目标中进行检验：（1）确定 Rbm38 如何差异调节 p63α 和 p63γ； (2)确定Rbm38是否调节TAp63和p63γ依赖的过早衰老和肿瘤抑制； (3)确定p63-Rbm38环如何被调控及其生物学意义。