The tyrosinase (Tyr) gene encodes the enzyme tyrosinase that catalyses the conversion of L-tyrosine into DOPA (3,4-dihydroxyphenylalanine)-quinone. The albino mutation abrogates functional activity of tyrosinase resulting in deficiency of melanin pigment production in skin and retina. Tyr maps to a region in the central position of Chromosome 7 that contains a skin tumor-modifier locus. We rescued the albino mutation in transgenic mice to assess a possible role of Tyr gene in two-stage skin carcinogenesis. Transgenic expression of the functional Tyr(Cys) allele in albino mice (Tyr(Ser)) caused a reduction in skin papilloma multiplicity, in four independent experiments and at three dose levels of DMBA (9,10-dimethyl-1,2-benzanthracene). In vitro mechanistic studies demonstrated that transfection of the Tyr(Cys) allele in a human squamous cell carcinoma cell line (NCI-H520) increases tyrosinase enzyme activity and confers resistance to hydrogen peroxide-induced oxidative DNA damage. These results provide direct evidence that the Tyr gene can act as a skin cancer-modifier gene, whose mechanism of action may involve modulation of oxidative DNA damage.
Titolo: | Loss of tyrosinase activity confers increased skin tumor susceptibility in mice |
Autori: | |
Parole Chiave: | Animal models; Genetic predisposition; Polymorphism |
Settore Scientifico Disciplinare: | Settore MED/01 - Statistica Medica |
Data di pubblicazione: | 20-mag-2004 |
Rivista: | |
Tipologia: | Article (author) |
Digital Object Identifier (DOI): | 10.1038/sj.onc.1207565 |
Appare nelle tipologie: | 01 - Articolo su periodico |