Loss of tyrosinase activity confers increased skin tumor susceptibility in mice.
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.
Biotechnology Unit, ENEA CR Casaccia, Rome, Italy.
Anna
A
Saran
Monica
M
Spinola
Simonetta
S
Pazzaglia
Bernard
B
Peissel
Cecilia
C
Tiveron
Laura
L
Tatangelo
Mariateresa
M
Mancuso
Vincenzo
V
Covelli
Lisa
L
Giovannelli
Vanessa
V
Pitozzi
Carmen
C
Pignatiello
Silvano
S
Milani
Piero
P
Dolara
Tommaso A
TA
Dragani
D000417:Albinism / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004249:DNA Damage; D020022:Genetic Predisposition to Disease; D051379:Mice; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
D014442:Monophenol Monooxygenase