The role of the p63-RBM38 loop in tumor suppression

P63是p53家族的肿瘤抑制因子。当p63从P1启动子表达时，产生5种TAp63亚型（α, β, γ, δ, ε）。当p63从p2启动子表达时，产生5个ΔNp63亚型。虽然RT-PCR可以检测到10种p63亚型的转录本，但只检测到p63α和p63γ的蛋白，因此是本研究的重点。TAp63包含一个在p53中保守的N端激活结构域，并调节一系列抑制生长的基因。事实上，缺乏TAp63的小鼠更容易发生自发性肿瘤和早衰。相反，ΔNp63含有独特的n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，并被归类为癌蛋白。Rbm38，也称为RNPC1，是一种RNA结合蛋白，具有一个RNA识别基序（RRM），是p63的靶标。有趣的是，我们发现Rbm38通过结合p63 3‘非翻译区（3’ utr）抑制p63α mRNA的稳定性。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起关键作用。该假设将在以下三个具体目的中进行检验：(1)确定

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.