Regulation of the transcription factor p63 by βTrCP

This study identifies SCFβTrCP1 as an E3 ubiquitin ligase that selectively stabilizes and activates the TAp63γ isoform. βTrCP1 increases TAp63γ protein levels and half-life through direct binding and K48‑linked ubiquitylation at the N‑terminus. This stabilization enhances TAp63γ‑driven p21 transcription and promotes G1/S cell‑cycle arrest. A ligase‑deficient βTrCP1 mutant blocks these effects, confirming ubiquitylation is required. Overall, these findings reveal a mechanism by which SCFβTrCP1 differentially regulates p63 isoforms, advancing understanding of p63’s role in epithelial homeostasis and cancer.