APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations
SourceProceedings of the National Academy of Sciences USA, 110, 6, (2013), pp. 2157-62
Article / Letter to editor
Display more detailsDisplay less details
Laboratory of Medical Immunology
Physical Organic Chemistry
Proceedings of the National Academy of Sciences USA
SubjectIGMD 3: Genomic disorders and inherited multi-system disorders; N4i 1: Pathogenesis and modulation of inflammation; N4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunity; N4i 4: Auto-immunity, transplantation and immunotherapy; NCMLS 6: Genetics and epigenetic pathways of disease; NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders; Physical Organic Chemistry
p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1(MET) (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.