Molecular Mechanisms of p63-Derived Ectodermal Dysplasia

Molecular defects in the p63 gene give rise to severe physiological abnormalities in patients with ectodermal dysplasia, however the mechanisms by which p63 mutations disrupt p63 function are unknown. In this study we examined four ΔNp63α mutants; Ectrodactyly-Ectodermal Dysplasia with Clefting (EEC) R204W, R304W and Ankyloblepharon-Ectodermal Dysplasia with Clefting (AEC) mutants, L514F and G530V, and characterized DNA binding, transcription factor activity, oligomerization with wild-type p63 and changes in protein stability/nuclear localization. We also investigated the putative OD-SAM interaction in p63 and p73. We demonstrated that both the EEC and AEC mutants cannot transcriptionally activate the PERP promoter and can hetero-oligomerize forming dominant negative complexes with wild-type p63. We show that both EEC mutants and AEC L514F mutants are more stable which is not due to aberrant degradation by the E3 ligase Itch. Finally, we discovered that a novel interaction between the p73 OD and SAM domain is absent in p63.MAS