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.