p63 is expressed from two promoters and produces two N-terminal isoforms, TAp63 and ΔNp63. Alternative splicing creates three C-terminal isoforms p63α, p63β, and p63δ, whereas alternative polyadenylation (APA) in coding sequence creates two more C-terminal isoforms p63γ and p63ε. 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 p63γ mRNA through APA in coding sequence. We also found that PABPN1 is necessary for p63α translation by modulating the binding of translation initiation factors eIF4E and eIF4G to p63α mRNA. Moreover, we found that the p53 family, especially p63α, 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 ΔNp63α. Finally, we found that PABPN1 controls the terminal differentiation of HaCaT keratinocytes by modulating ΔNp63α 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.

p63 由两个启动子表达并产生两个 N 端同工型，TAp63 和 ΔNp63。选择性剪接产生三种 C 端同种型 p63α、p63β 和 p63δ，而编码序列中的选择性多聚腺苷酸化 (APA) 产生另外两种 C 端同种型 p63γ 和 p63ε。尽管已经鉴定出几种转录因子可以差异调节 N 端 p63 同种型，但尚不清楚 C 端 p63 同种型是如何受到调节的。因此，我们确定了 APA 的关键调节因子 PABPN1 是否可以差异调节 C 端 p63 同种型。我们发现 PABPN1 缺乏通过编码序列中的 APA增加p63 γ mRNA。我们还发现 PABPN1 通过调节翻译起始因子 eIF4E 和 eIF4G 与p63 α mRNA。此外，我们发现p53家族，尤其是p63α，调节PABPN1的转录，表明p63和PABPN1之间的相互调节形成了一个反馈回路。此外，我们发现 PABPN1 缺乏会抑制角质形成细胞的生长，这可以通过异位 ΔNp63α 来挽救。最后，我们发现 PABPN1 通过调节 ΔNp63α 表达来控制 HaCaT 角质形成细胞的终末分化。总之，我们的研究结果表明，PABPN1 是通过 APA 在编码序列和 mRNA 翻译中 C 端 p63 同种型的关键调节因子，并且 p63-PABPN1 环调节 p63 活性和 APA 格局。