Increased susceptibility to skin carcinogenesis associated with a spontaneous mouse mutation in the palmitoyl transferase Zdhhc13 gene

Carlos J. Perez, Lars Mecklenburg, Jean Jaubert, Lucia Martinez-Santamaria, Brian M. Iritani, Alexsandra Espejo, Eleonora Napoli, Gyu Song, Marcela Del Río, John DiGiovanni, Cecilia R Giulivi, Mark T. Bedford, Sharon Y R Dent, Richard D. Wood, Donna F. Kusewitt, Jean Louis Guénet, Claudio J. Conti, Fernando Benavides

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13 luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13 luc /Zdhhc13 luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis, and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared with wild-type (WT) epidermis in untreated skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical skin carcinogenesis were significantly higher in mutant mice than WT littermates. To our knowledge, this is the first report of a protective role for PAT in skin carcinogenesis.

Original languageEnglish (US)
Pages (from-to)3133-3143
Number of pages11
JournalJournal of Investigative Dermatology
Volume135
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Perez, C. J., Mecklenburg, L., Jaubert, J., Martinez-Santamaria, L., Iritani, B. M., Espejo, A., Napoli, E., Song, G., Del Río, M., DiGiovanni, J., Giulivi, C. R., Bedford, M. T., Dent, S. Y. R., Wood, R. D., Kusewitt, D. F., Guénet, J. L., Conti, C. J., & Benavides, F. (2015). Increased susceptibility to skin carcinogenesis associated with a spontaneous mouse mutation in the palmitoyl transferase Zdhhc13 gene. Journal of Investigative Dermatology, 135(12), 3133-3143. https://doi.org/10.1038/jid.2015.314