UV exposure, genetic targets in melanocytic tumors and transgenic mouse models.
The genetic changes and corruption of kinase activity in melanomas appear to revolve around a central axis: mitogenic signaling along the RAS pathway down to transcription regulation by pRB. Epidemiological studies point to the importance of ultraviolet (UV) radiation in the etiology of melanoma, but where and how UV radiation is targeted to contribute to the oncogenic signaling remains obscure. Animal models of melanoma genesis could serve to clarify this issue, but many of these models are not responsive to UV exposure. Most interesting advances have been made by using transgenic mice that carry genetic defects that are known to be relevant to human melanoma: specifically, dysfunction in the tumor suppressive action of p16INK4a or a receptor tyrosine kinase/RAS pathway, that is constitutively activated in melanocytes. The latter types of mice appear to be most responsive to (neonatal) UV exposure. Whether this is due to a general increase in target cells by melanocytosis and a paucity or complete lack of pigment, or a possible UV-induced response of the promoter-enhancer of the transgene or a genuinely independent and additional genetic alteration caused by UV exposure needs to be established. Importantly, the full effect of UV radiation needs to be ascertained in mice with different pigmentation by varying the wavelengths, UV-B versus UV-A1, and the exposure schedules, i.e. neonatal versus adult and chronic versus intermittent overexposure. Intermittent UV-B overexposure deserves special attention because it most strongly evokes proliferative responses in melanocytes.
de Gruijl
Frank R
FR
Department of Dermatology, Leiden University Medical Center/LUMC, Sylvius Labs, Room 3038, Wassenaarseweg 72, NL-2333 AL Leiden, The Netherlands. degruijl@wxs.nl
van Kranen
Henk J
HJ
van Schanke
Arne
A
D000818:Animals; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics*; D014466:Ultraviolet Rays