The researchers report in Cell that when p53 is activated (in response to DNA damage caused by the sun's ultraviolet (UV) rays and other factors), it triggers production of alpha-MSH, a hormone that then prompts production of melanin, or pigment. Recognizing that p53 is the linchpin of this chain of events could result in a way to "give people tans without needing the sun" (or creams or sprays to artificially color their skin), says senior study author David Fisher, director of Dana-Farber's Cutaneous Oncology and Melanoma Program.
In many types of cancer, p53 is disabled and cannot fulfill its role as a tumor suppressor. Deprived of their ability to fix new DNA damage, defective cells often become tumor cells and proliferate unchecked. In the case of skin cancer—which Fisher notes is "the most common and most preventable" form of the disease—the ability to tan is an extremely strong predictor of cancer susceptibility: Fair-skinned people who are more likely to burn than tan in the sun are at higher risk of developing skin cancer than individuals who tan easily.
In work published last year, the Dana-Farber group found that alpha-MSH, needed to induce melanin production, does not come from melanocytes (melanin-producing cells in the skin). They believe the hormone, instead, is produced in keratinocytes, the most common type of skin cells. The reason: they found broken alpha-MSH receptors on the surface of melanocytes in subjects with an inability to tan.
Other lab work had shown that p53 activates during tanning. And, sure enough, when the Dana-Farber team probed the protein pro-opiomelanocortin (POMC)—which splits to make several hormones including alpha-MSH—it discovered "a perfect p53 binding element there," Fisher says. When testing both mouse and human keratinocytes in vitro, the team observed that after six hours of exposure to UV radiation, p53, POMC and alpha-MSH levels had all jumped dramatically, with the latter's rising 30 times higher than normal. The finding was confirmed in knockout mice missing the gene that codes for p53: Without the protein, POMC was never activated, the mice did not tan (on their hairless ears and tails), and eventually they all developed melanomas.
"What we were stumbling into here was actually a role for p53 in absolutely normal cells," Fisher says, "and it's a normal physiologic response that happens anytime any of us walks out of the house in the morning." He adds that people have a "love-hate relationship" with UV rays, which stimulate vitamin D production needed to keep bones strong and healthy, but also cause potentially deadly skin cancer and premature wrinkling.
Barbara Gilchrest, chair of the Department of Dermatology at Boston University School of Medicine, says that the new findings demonstrate that the p53 system is a broad-response mechanism that has both reparative and preventative properties for DNA damage. "When you damage DNA in cells, they not only work very hard to fix that DNA, but they also work hard to prepare the cell and tissue to be resistant to future DNA damage," she says. "Once you have that tan, your DNA is better protected for the next time that you're out in the sun, because of that melanin cover over the nucleus shielding it from UV rays that would damage [the] DNA inside."
Fisher says that, in theory, the p53 pathway could be a "druggable" one. "In fact, one of the directions that we're taking to use this information is to try to identify small molecules that could potentially be delivered topically," he reveals, "to either increase or decrease pigmentation through interfering [with] or mimicking this pathway."