FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α 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 ΔNp63α functions. Here we show that the p300 acetyl-transferase physically interacts in vivo with ΔNp63α and catalyzes its acetylation on lysine 193 (K193) inducing ΔNp63α 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 ΔNp63α to the tyrosine kinase c-Abl as well as the levels of ΔNp63α acetylation. Notably, the natural mutant ΔNp63α-K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway. This mutant ΔNp63α protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated ΔNp63α target genes. Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls ΔNp63α 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.
Mesh Terms:
Animals, Cell Line, Congenital Abnormalities, DNA-Binding Proteins, Embryonic Development, Fibroblast Growth Factor 8, Gene Expression Regulation, Neoplastic, Humans, Limb Deformities, Congenital, Mice, Mutation, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-abl, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins, p300-CBP Transcription Factors
Animals, Cell Line, Congenital Abnormalities, DNA-Binding Proteins, Embryonic Development, Fibroblast Growth Factor 8, Gene Expression Regulation, Neoplastic, Humans, Limb Deformities, Congenital, Mice, Mutation, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-abl, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins, p300-CBP Transcription Factors
Hum. Mol. Genet.
Date: Aug. 01, 2015
PubMed ID: 25911675
View in: Pubmed Google Scholar
Download Curated Data For This Publication
198929
Switch View:
- Interactions 2