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.
Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy.
Michela
M
Restelli
Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy.
Elisa
E
Molinari
Dermatology Unit, NESMOS Department, Università di Roma La Sapienza, I-00189 Rome, Italy and.
Barbara
B
Marinari
Department of Molecular Biotechnologies and Health Sciences, Università di Torino, I-10126 Torino, Italy.
Daniele
D
Conte
Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy.
Nerina
N
Gnesutta
Dermatology Unit, NESMOS Department, Università di Roma La Sapienza, I-00189 Rome, Italy and.
Antonio
A
Costanzo
Department of Molecular Biotechnologies and Health Sciences, Università di Torino, I-10126 Torino, Italy.
Giorgio Roberto
GR
Merlo
Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy, luisa.guerrini@unimi.it.
Luisa
L
Guerrini
D000818:Animals; D002460:Cell Line; D000013:Congenital Abnormalities / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D051524:Fibroblast Growth Factor 8 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C496456:FGF8 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051524:Fibroblast Growth Factor 8; D050880:p300-CBP Transcription Factors; D016315:Proto-Oncogene Proteins c-abl