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P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome.

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.

Pubmed ID: 12692135


  • Fomenkov A
  • Huang YP
  • Topaloglu O
  • Brechman A
  • Osada M
  • Fomenkova T
  • Yuriditsky E
  • Trink B
  • Sidransky D
  • Ratovitski E


The Journal of biological chemistry

Publication Data

June 27, 2003

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01-AI47224
  • Agency: NIDCR NIH HHS, Id: R01-DE13561

Mesh Terms

  • Abnormalities, Multiple
  • Animals
  • Cell Differentiation
  • DNA-Binding Proteins
  • Ectodermal Dysplasia
  • Epithelial Cells
  • Gene Expression Regulation
  • Genes, Tumor Suppressor
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Humans
  • Membrane Proteins
  • Mice
  • Mouth Abnormalities
  • Mutation
  • Phosphoproteins
  • Protein Binding
  • Protein Isoforms
  • Protein Splicing
  • RNA-Binding Proteins
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptors, Fibroblast Growth Factor
  • Syndrome
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Two-Hybrid System Techniques