Abstract
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 TyrCys allele in albino mice (TyrSer) 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.
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Abbreviations
- DMBA:
-
9,10-dimethyl-1,2-benzanthracene
- DOPA:
-
3,4-dihydroxyphenylalanine
- Skts1 :
-
skin tumor susceptibility 1
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- Tyr :
-
tyrosinase
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Acknowledgements
We thank G Schutz for the gift of the phsTyr4 vector and Raffaella Coccia for help in the tyrosinase enzymatic assay. This work was partially funded by grants from European Commission (Association Contract FIGH-CT99-00006) and from Associazione and Fondazione Italiana Ricerca Cancro (AIRC and FIRC, Italy). Transgenic Mice Service Center is supported by Telethon Foundation (project B.55 to CT).
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Saran, A., Spinola, M., Pazzaglia, S. et al. Loss of tyrosinase activity confers increased skin tumor susceptibility in mice. Oncogene 23, 4130–4135 (2004). https://doi.org/10.1038/sj.onc.1207565
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DOI: https://doi.org/10.1038/sj.onc.1207565
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