Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene.
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 (Zdhhc13luc) 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 Zdhhc13luc/Zdhhc13luc 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.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Carlos J
CJ
Perez
Mecklenburg-consulting, Hamburg, Germany.
Lars
L
Mecklenburg
Unité de Génétique Fonctionnelle de la Souris, Institut Pasteur, Paris, France.
Jean
J
Jaubert
Department of Bioengineering, Universidad Carlos III de Madrid, Madrid, Spain; Regenerative Medicine Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
Lucia
L
Martinez-Santamaria
The Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
Brian M
BM
Iritani
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Alexsandra
A
Espejo
Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, USA.
Eleonora
E
Napoli
Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, USA.
Gyu
G
Song
Department of Bioengineering, Universidad Carlos III de Madrid, Madrid, Spain; Regenerative Medicine Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
Marcela
M
Del Río
Dell Pediatric Research Institute, University of Texas, Austin, Texas, USA.
John
J
DiGiovanni
Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, USA; Medical Investigations of Neurodevelopmental Disorders (M. I. N. D.) Institute, University of California Davis, Sacramento, California, USA.
Cecilia
C
Giulivi
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
Mark T
MT
Bedford
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
Sharon Y R
SYR
Dent
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
Richard D
RD
Wood
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
Donna F
DF
Kusewitt
Unité de Génétique Fonctionnelle de la Souris, Institut Pasteur, Paris, France.
Jean-Louis
JL
Guénet
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; Department of Bioengineering, Universidad Carlos III de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
Claudio J
CJ
Conti
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA. Electronic address: fbenavid@mdanderson.org.
Fernando
F
Benavides
D000217:Acyltransferases / Q000235:genetics*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D018388:Codon, Terminator; D000078404:Epidermal Cells; D020022:Genetic Predisposition to Disease; D015603:Keratinocytes / Q000502:physiology; D019272:Leukocyte Elastase / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D041681:NIH 3T3 Cells; D020556:Neutrophil Infiltration; D010641:Phenotype; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*
D018388:Codon, Terminator; D016328:NF-kappa B; D000217:Acyltransferases; C552301:Zdhhc13 protein, mouse; D019272:Leukocyte Elastase; D001973:Bromodeoxyuridine