The role of the p63-RBM38 loop in tumor suppression

P63是一种P53家族肿瘤抑制因子。当p63从P1启动子表达时，产生五种TAp63亚型(α，β，γ，δ，ε)。当p63从P2启动子中表达时，产生五种ΔNp63亚型。虽然RT-PCR法可以检测到10种p63亚型的转录本，但只有p63α和p63γ的蛋白被发现可检测到，因此是研究的重点。TAp63含有一个在P53中保守的N-末端激活结构域，并调节一系列抑制生长的基因。事实上，缺乏TAp63的小鼠很容易发生自发性肿瘤和过早衰老。相反，ΔNp63含有一个独特的N-末端激活结构域，是表皮和其他层状上皮细胞正常发育所必需的。此外，ΔNp63在癌症中过表达，并被归类为癌蛋白。Rbm38，又称RNPC1，是一种具有一个RNA识别基序(RRM)的RNA结合蛋白，以p63为靶标。有趣的是，我们发现Rbm38通过与p63 3‘非翻译区(3’α)结合来抑制p63 UTRmRNA的稳定性。因此，p63和Rbm38之间的相互调节提示我们假设p63-Rbm38环在p63依赖的肿瘤抑制和长寿中发挥关键作用。这一假设将在以下三个具体目标中进行检验：(1)确定 目的：(1)研究Rbm38对p63-α和p63-γ的调控作用；(2)确定Rbm38是否调控依赖γ的早衰和肿瘤抑制；(3)确定p63-Rbm38环的调控方式及其生物学意义。

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.