Tanning trigger.
The ears of normal mice tan under UV light (top), but the ears of mice lacking p53 remain pale (bottom).

Rutao Cui

Anti-Cancer Gene Triggers Tanning

A tan is more than a sign of sun damage. It's also a natural shield against skin cancer, particularly the deadliest sort: melanoma. Now scientists have found another surprising link between tanning and cancer: p53--a gene long implicated as a cancer suppressor--appears to be key to helping us tan.

The simple act of catching a few rays sets a complex biological process into motion. In response to ultraviolet (UV) light from the sun, skin cells called kerotinocytes begin pumping out melanocyte-stimulating hormone (MSH), which in turn binds to MSH receptors on pigment-producing skin cells called melanocytes. This starts a cascade of events that leads to melanin production and a nice brown tan. Defective forms of the MSH receptor are strongly associated with red hair and the inability to tan. (Science, 2 March 2007)

Pediatric oncologist David Fisher at the Dana Farber Cancer Institute in Boston, Massachusetts, wanted to find out what caused MSH levels to rise in the first place. Because MSH is derived from a gene called pro-opiomelanocortin (POMC), Fisher, along with postdoctoral fellow Rutao Cui and their colleagues, combed POMC's sequence, looking for places where regulators of gene activity might attach. To their delight, they found a binding region for the p53 protein in rat, mouse, and human versions of the gene.

Artificially raising levels of p53 in cells boosted POMC expression, the researchers found, buttressing the idea that p53 activates POMC. And when the scientists exposed mice lacking p53 to UV light, the mice failed to tan on their ears and tails (the body parts that contain melanocytes). By contrast, normal mice tanned well in those spots, indicating that p53 is necessary for tanning, the team reports in tomorrow's issue of Cell.

In other experiments, the researchers exposed human skin samples to UV and measured levels of p53, MSH, and a downstream protein called MITF, which turns on pigment genes in melanocytes. They saw p53 within 1 hour, followed by MSH at 3 hours, and then at 6 hours, MITF finally emerged, validating the notion that p53 is an early tanning trigger. Levels of p53 itself, Fisher says, increase in response to UV because the radiation switches on a DNA damage pathway that stabilizes p53, extending its life in the cell.

In turning on POMC, p53 coincidentally prompts production of the peptide beta-endorphin, the brain's natural opiate and another POMC product. Fisher is investigating whether this opiate functions as a local anesthetic to dull the pain of UV-induced inflammation. A more far-fetched idea: It acts in the brain to promote addictive, sun-seeking behavior.

Barbara Gilchrest, a dermatologist at Boston University School of Medicine, says the work fills in a dotted line in an important tanning mechanism and expands the role of p53 as DNA guardian. "p53 not only fixes the damage you've got, but also protects against similar damage in the future" through tanning, she says.

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