PABPN1, a Target of p63, Modulates Keratinocyte Differentiation through Regulation of p63α mRNA Translation

[摘要] p63 is expressed from two promoters and produces two N-terminal isoforms, TAp63 and Delta Np63. Alternative splicing creates three C-terminal isoforms p63 alpha, p63 beta, and p63 delta, whereas alternative polyadenylation (APA) in coding sequence creates two more C-terminal isoforms p63 gamma and p63 epsilon. Although several transcription factors have been identified to differentially regulate the N-terminal p63 isoforms, it is unclear how the C-terminal p63 isoforms are regulated. Thus, we determined whether PABPN1, a key regulator of APA, may differentially regulate the C-terminal p63 isoforms. We found that PABPN1 deficiency increases p63 gamma mRNA through APA in coding sequence. We also found that PABPN1 is necessary for p63 alpha translation by modulating the binding of translation initiation factors eIF4E and eIF4G to p63 alpha mRNA. Moreover, we found that the p53 family, especially p63 alpha, regulates PABPN1 transcription, suggesting that the mutual regulation between p63 and PABPN1 forms a feedback loop. Furthermore, we found that PABPN1 deficiency inhibits keratinocyte cell growth, which can be rescued by ectopic Delta Np63 alpha. Finally, we found that PABPN1 controls the terminal differentiation of HaCaT keratinocytes by modulating Delta Np63 alpha expression. Taken together, our findings suggest that PABPN1 is a key regulator of the C-terminal p63 isoforms through APA in coding sequence and mRNA translation and that the p63-PABPN1 loop modulates p63 activity and the APA landscape.

[发布日期] 2020-11-01