APR-246/PRIMA-1MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

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APR-246/PRIMA-1MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Authors
  • Jinfeng Shen
  • J. Shen
  • E. H. van den Bogaard
  • E. N. Kouwenhoven
  • V. J. N. Bykov
  • T. Rinne
  • Q. Zhang
  • G. S. Tjabringa
  • C. Gilissen
  • S. J. van Heeringen
  • J. Schalkwijk
  • H. van Bokhoven
  • K. G. Wiman
  • H. Zhou
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Volume
110
Issue
6
Pages
2157–2162
Identifiers
DOI: 10.1073/pnas.1201993110
Source
AIMS
Keywords
License
Unknown

Abstract

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 com-pound 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 charac-terization 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.

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