p63 is a p53 family tumor suppressor. When p63 is expressed from the P1 promoter, five TAp63 isoforms ??????????????? are produced. When p63 is expressed from theP2 promoter, five ?Np63 isoforms are produced. While the transcripts for ten p63 isoforms can be detected by RT-PCR, only proteins for p63? and p63? 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, ?Np63, which contains a unique N-terminal activation domain, is required for proper development of epidermis and other stratified epithelial cells. Additionally, ?Np63 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 p63? 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 p63? and p63? are differentially regulated by Rbm38; (2) to determine whether Rbm38 regulates TAp63- and p63?-dependent premature aging and tumor suppression; (3) to determine how the p63-Rbm38 loop is regulated and its biological significance.
p63 is a member of the p53 tumor suppressor family and known to play a role in tumor suppression. The proposed study is to determine the role of the p63-Rbm38 loop in tumor suppression and premature aging. Listed below are some of the rationales why the proposed study is relevant to human health. First, p63 is expressed as ten isoforms, which are differentially expressed in various cell types and tissues. In addition, these p63 isoforms have distinct transcriptional and biological activities. Thus, how these p63 isoforms are differentially regulated by Rbm38 via their 3'-untranslated regions (3'UTRs) may provide an insight into the mechanism by which the expression patterns and biological activities of these p63 isoforms are regulated. Second, understanding how the p63-Rbm38 loop is regulated by the Akt pathway may provide an insight into how Akt inhibitors suppress tumor formation, especially considering that Akt inhibitors are being tested in multiple clinical trials. Third, Rbm8 is an ideal molecule to modulate p63 expression and may be explored as a target for managing cancer and extending longevity.
