A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias

Moretti, F., Marinari, B., Iacono, N. L., Botti, E., Giunta, A., Spallone, G., Garaffo, G., Vernersson-Lindahl, E., Merlo, G., Mills, A. A., Ballaro, C., Alema, S., Chimenti, S., Guerrini, L., Costanzo, A. (May 2010) A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias. Journal of Clinical Investigation, 120 (5). pp. 1570-1577.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/20424325
DOI: 10.1172/JCI40267

Abstract

The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankyloblepharon ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary keratinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the ΔNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasomemediated ΔNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, thereby limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation- differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.

Item Type: Paper
Uncontrolled Keywords: human congenital syndromes Interferon regulatory factor 6
Subjects: diseases & disorders > cancer
diseases & disorders > congenital hereditary genetic diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p63
CSHL Authors:
Communities: CSHL labs > Mills lab
CSHL Cancer Center Shared Resources > Animal Services
Depositing User: Matt Covey
Date: 3 May 2010
Date Deposited: 11 Mar 2013 20:35
Last Modified: 29 Dec 2014 19:43
PMCID: PMC2860936
Related URLs:
URI: https://repository.cshl.edu/id/eprint/27763

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