"The number one risk factor for melanoma is an inability to tan; people who tan easily or have dark pigmentation are far less likely to develop the disease," says the study's senior author, David E. Fisher, MD, PhD, director of the Melanoma Program at Dana-Farber and a professor in pediatrics at Children's Hospital Boston. "This study suggests that p53, one of the best-known tumor-suppressor proteins in our body, has a powerful role in protecting us against sun damage in the skin."

In a study published last year, Fisher and his colleagues found that ultraviolet (UV) radiation from the sun causes skin cells called keratinocytes to make and secrete a hormone called a-MSH, which attaches to nearby skin cells called melanocytes and spurs them to produce melanin, the pigment that darkens skin. The chain of events that leads to a-MSH production, however, was a mystery.

Investigators knew that a-MSH is created when another protein called pro-opiomelanocortin (POMC) is split apart. They also knew that the amount of POMC within cells rises sharply when they're exposed to UV rays. But they didn't know what caused the POMC to increase.

One possibility was p53. When Fisher and his colleagues examined the section of the gene for POMC that promotes production of the protein, they found it meshed nicely with p53 -- suggesting that when p53 docks there, it revs up POMC production. Additional evidence came when the researchers exposed human and mouse keratinocytes to UV radiation: After six hours, levels of both POMC and p53 were far higher than normal, and the level of pigment-stimulating a-MSH was 30 times above normal.

The implications of the research go beyond tanning. A variety of skin conditions are associated with the formation of dark spots that are unrelated to sun exposure. The spots arise when groups of cells begin producing pigment in response to repeated stress or irritation of the skin -- mimicking the tanning response. Although not dangerous, the condition can be a cosmetic problem, depending on its location.

"Our research offers a potential explanation of how this condition -- known as post-inflammatory hyperpigmentation -- occurs," Fisher says. "We know that it occurs as a result of stress, and p53 is a classic 'stress' protein, going into action when cells experience stress-related DNA damage. What we've learned about p53 suggests that it may trigger the hyperpigmentation process."

There is even the possibility that p53 protects against skin damage in a second -- and previously unsuspected -- way. The protein not only causes skin to tan in response to sunlight, it may also underlie people's desire to spend time in the sun. Spending time in the sun may be protective in people who tan easily.

The same process that causes POMC to produce a-MSH also leads to the production of b-endorphin, a natural opiate in the body that may be associated with feelings of pleasure. "Even as p53 causes skin to tan during sunlight exposure, it may also affect neuronal circuits," Fisher says. "These proteins may provide an explicit link between the regulation of tanning and of mood. It raises the question of whether p53-mediated induction of b-endorphin is involved in sun-seeking behavior, which often increases skin cancer risk."

The study's lead author is Rutao Cui, MD, PhD, of Dana-Farber and Children's Hospital Boston. Co-authors include Hans Widlund, PhD, Erez Feige, PhD, Jennifer Lin, MD, Dara Wilensky, Vivien Igras, and John D'Orazio, MD, PhD, formerly of Dana-Farber and Children's and now at the University of Kentucky College of Medicine; Scott Granter, MD, of Dana-Farber and Brigham and Women's Hospital; Claire Fung, MD, of Massachusetts General Hospital; and Carl Schanbacher, MD, of Brigham and Women's.

The research was supported by a grant from the National Institutes of Health, and the Doris Duke Charitable Foundation.

Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: www.childrenshospital.org/newsroom.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.