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，产生五种TAp 63同种型（α、β、γ、δ、ε）。当p63由P2启动子表达时，产生五种Δ Np 63亚型。虽然10种p63亚型的转录本可以通过RT-PCR检测到，但仅发现p63α和p63γ蛋白是可检测的，因此是研究的重点。TAp 63含有一个在p53中保守的N-末端激活结构域，并调节一系列生长抑制基因。事实上，缺乏TAp 63的小鼠容易发生自发性肿瘤和过早衰老。相比之下，Δ Np 63含有独特的N-末端激活结构域，是表皮和其他复层上皮细胞正常发育所必需的。此外，Δ Np 63在癌症中过表达，并被归类为一种癌蛋白。Rbm 38，也称为RNPC 1，是一种RNA结合蛋白，具有一个RNA识别基序（RRM）和p63靶点。有趣的是，我们发现Rbm 38通过与p63 3 3'非翻译区（3' UTR）结合来抑制p63α mRNA的稳定性。因此，p63和Rbm 38之间的相互调节促使我们假设p63-Rbm 38环在p63依赖性肿瘤抑制和寿命中起关键作用。该假设将在以下三个具体目标进行测试：（1）确定 Rbm 38对p63α和p63γ的调节作用;（2）Rbm 38是否调节TAp 63和p63γ依赖的早衰和肿瘤抑制作用;（3）p63-Rbm 38环的调节作用及其生物学意义。

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.