Abstract
p63, a p53 family member, is required for craniofacial and limb development as well as proper skin differentiation. However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Wells syndrome) were found in the p63 carboxyl-terminal region with a sterile alpha-motif. By two-hybrid screen we identified several proteins that interact with the p63alpha carboxyl terminus and its sterile alpha-motif, including the apobec-1-binding protein-1 (ABBP1). AEC-associated mutations completely abolished the physical interaction between ABBP1 and p63alpha. Moreover the physical association of p63alpha and ABBP1 led to a specific shift of FGFR-2 alternative splicing toward the K-SAM isoform essential for epithelial differentiation. We thus propose that a p63alpha-ABBP1 complex differentially regulates FGFR-2 expression by supporting alternative splicing of the K-SAM isoform of FGFR-2. The inability of mutated p63alpha to support this splicing likely leads to the inhibition of epithelial differentiation and, in turn, accounts for the AEC phenotype.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abnormalities, Multiple / genetics*
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Animals
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Cell Differentiation
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DNA-Binding Proteins
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Ectodermal Dysplasia / genetics
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Epithelial Cells / cytology
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Gene Expression Regulation
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Genes, Tumor Suppressor
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B
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Humans
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Membrane Proteins*
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Mice
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Mouth Abnormalities / genetics
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Mutation
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Protein Binding / genetics
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Splicing*
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RNA-Binding Proteins / metabolism*
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Receptor, Fibroblast Growth Factor, Type 2
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Receptors, Fibroblast Growth Factor / biosynthesis*
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Receptors, Fibroblast Growth Factor / physiology
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Syndrome
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Transcription Factors
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Tumor Suppressor Proteins
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Two-Hybrid System Techniques
Substances
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CKAP4 protein, human
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DNA-Binding Proteins
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HNRNPAB protein, human
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B
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Membrane Proteins
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Phosphoproteins
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Protein Isoforms
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RNA-Binding Proteins
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Receptors, Fibroblast Growth Factor
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TP63 protein, human
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Trans-Activators
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Transcription Factors
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Trp63 protein, mouse
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Tumor Suppressor Proteins
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Receptor, Fibroblast Growth Factor, Type 2
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keratinocyte growth factor receptor