FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the Delta Np63 alpha protein

The p63 transcription factor, homolog to the p53 tumor suppressor gene, plays a crucial role in epidermal and limb development, as its mutations are associated to human congenital syndromes characterized by skin, craniofacial and limb defects. While limb and skin-specific p63 transcriptional targets are being discovered, little is known of the post-translation modifications controlling Delta Np63 alpha functions. Here we show that the p300 acetyl-transferase physically interacts in vivo with Delta Np63 alpha and catalyzes its acetylation on lysine 193 (K193) inducing Delta Np63 alpha stabilization and activating specific transcriptional functions. Furthermore we show that Fibroblast Growth Factor-8 (FGF8), a morphogenetic signaling molecule essential for embryonic limb development, increases the binding of Delta Np63 alpha to the tyrosine kinase c-Abl as well as the levels of Delta Np63 alpha acetylation. Notably, the natural mutant Np63 alpha-K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway. This mutant Delta Np63 alpha protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated Delta Np63 alpha target genes. Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls Delta Np63 alpha protein stability and transcriptional activity. Hence, limb malformation-causing p63 mutations, such as the K193E mutation, are likely to result in aberrant limb development via the combined action of altered protein stability and altered promoter occupancy.

24(15):4185-97. doi: 10.1093/hmg/ddv151. Epub 2015 Apr 24. PubMed PMID:25911675; PubMed Central PMCID: PMC4492388.