Publication in PNAS

Zhou Etc

A joint team of researchers in the NCMLS led by Jo Huiqing Zhou, involving the Departments of Molecular Developmental Biology, Human Genetics, and Dermatology has shown that a compound targeting p53 mutants to restore the pro-apoptotic activity of p53, APR246/PRIMA-1MET, is able to rescue differentiation defects in skin epidermal cells carrying p63 mutations. This work was published with a shared first authorship of Ellen van den Bogaard and Evelyn Kouwenhoven, in the Proceedings of the National Academy of Sciences USA, and was the result of a collaboration with Klas Wiman's group at the Karolinska Institute, Sweden, who initially identified this compound.

p53 and p63 proteins share extensive sequence and structure homology. Whereas  p53 mutations are a hallmark of many cancers, mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects and orofacial clefting. The amino acid residues that are most frequently mutated in p53 in cancers correspond to the residues that are hot-spot mutations in p63 and that are associated with a genetic disorder called EEC syndrome. Therefore, it was hypothesized that a compound APR246/PRIMA-1MET targeting p53 mutant protein for cancer treatment (in a phase I/II clinical trial) may similarly re-activate p63 mutants in EEC syndrome. Treatment of epidermal cells from skin basal epithelium (keratinocytes) of EEC patients with APR246/PRIMA-1MET partially but consistently rescued morphological features and gene expression during epidermal stratification. This work suggests a novel concept of developing targeted therapy for phenotypically distinct diseases that are caused by a similar underlying molecular mechanism.

This paper has been published back-to-back with another paper using induced pluripotent stem cells (iPSCs) established from p63 patients as a model (Daniel Aberdam's group in Israel). Treatment with APR246/PRIMA-1MET on p63 iPSC-derived corneal epithelial cells rescues differentiation defects in these cells.

These papers can be found:

1. Published online before print January 25, 2013, doi: 10.1073/pnas.1201993110 PNAS January 25, 2013 201201993;

2. Published online before print January 25, 2013, doi: 10.1073/pnas.1201753109 PNAS January 25, 2013 201201753.

 


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