title: A dominant mutation etiologic for human tricho-dento-osseous syndrome impairs the ability of DLX3 to downregulate ΔNp63α.
abstract: The homeodomain transcription factors play crucial roles in many developmental processes ranging from organization of the body plan to differentiation of individual tissues. The homeodomain protein Distal-less-3 (DLX3) has an essential role in epidermal stratification and development of ectodermal appendages, placenta and bones. A four-nucleotide deletion in the human DLX3 gene is etiologic for the human hereditary tricho-dento-osseous (TDO) ectodermal dysplasia, a dominant syndrome characterized by abnormalities in hair, nails, teeth, and bones. We have previously demonstrated that DLX3 gene expression induces degradation of ΔNp63α, a specific product of the TP63 gene, a master regulator of multi-layered epithelia. Here we show that the DLX3(TDO) mutant protein is unable to promote ΔNp63α protein degradation and impairs the expression of cell cycle regulatory proteins and skin differentiation markers. However, we found that in cell expressing equal amounts of mutant and wild-type DLX3, ΔNp63α protein level is efficiently regulated implying that genetic heterozygosity at the DLX3 locus protects TDO patients from developing severe p63-associated skin defects.
authors.affiliation: Department of Structural and Molecular Biology, University of Naples, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Costanzo
authors.forename: Luisa
authors.initials: L
authors.lastname: Festa
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Roscigno
authors.forename: Maria
authors.initials: M
authors.lastname: Vivo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pollice
authors.forename: Maria
authors.initials: M
authors.lastname: Morasso
authors.forename: Girolama
authors.initials: G
authors.lastname: La Mantia
authors.forename: Viola
authors.initials: V
authors.lastname: Calabrò
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D019465:Craniofacial Abnormalities; D003744:Dental Enamel Hypoplasia / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004476:Ectodermal Dysplasia / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006201:Hair Diseases / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017384:Sequence Deletion / Q000235:genetics; D012867:Skin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins