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.
FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α protein / M. Restelli, E. Molinari, B. Marinari, D. Conte, N. Gnesutta, A. Costanzo, G. Merlo, L. Guerrini. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 24:15(2015 Aug 01), pp. 4185-4197.
|Titolo:||FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α protein|
|Parole Chiave:||p63; limb development; p300|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||1-ago-2015|
|Data ahead of print / Data di stampa:||24-apr-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/hmg/ddv151|
|Appare nelle tipologie:||01 - Articolo su periodico|