TY - JOUR
T1 - Loss of tyrosinase activity confers increased skin tumor susceptibility in mice
AU - Saran, Anna
AU - Spinola, Monica
AU - Pazzaglia, Simonetta
AU - Peissel, Bernard
AU - Tiveron, Cecilia
AU - Tatangelo, Laura
AU - Mancuso, Mariateresa
AU - Covelli, Vincenzo
AU - Giovannelli, Lisa
AU - Pitozzi, Vanessa
AU - Pignatiello, Carmen
AU - Milani, Silvano
AU - Dolara, Piero
AU - Dragani, Tommaso A.
PY - 2004/5/20
Y1 - 2004/5/20
N2 - The tyrosinase (Tyr) gene encodes the enzyme tyrosinase that catalyses the conversion of L-tyrosine into DOPA (3,4-dihydroxypheaylalanine)-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 TyrCys 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 TyrCys 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.
AB - The tyrosinase (Tyr) gene encodes the enzyme tyrosinase that catalyses the conversion of L-tyrosine into DOPA (3,4-dihydroxypheaylalanine)-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 TyrCys 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 TyrCys 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.
KW - Animal models
KW - Genetic predisposition
KW - Polymorphism
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U2 - 10.1038/sj.onc.1207565
DO - 10.1038/sj.onc.1207565
M3 - Article
C2 - 15007389
AN - SCOPUS:2942554806
VL - 23
SP - 4130
EP - 4135
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 23
ER -