Publication Date:
2015-07-07
Description:
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 Np63 α functions. Here we show that the p300 acetyl-transferase physically interacts in vivo with Np63 α and catalyzes its acetylation on lysine 193 (K193) inducing Np63 α 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 Np63 α to the tyrosine kinase c-Abl as well as the levels of Np63 α acetylation. Notably, the natural mutant Np63 α -K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway. This mutant Np63 α protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated Np63 α target genes. Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls Np63 α 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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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