The team discovered in studies of mice and human skin that p53, a gene best known for keeping tumors at bay, is ultimately responsible for activating the tanning machinery that darkens the skin of so many sun-seeking beachgoers, thereby protecting them from sunburns.
"The p53 tumor suppressor is commonly mutated in human cancer," explained David Fisher, director of the Melanoma Program in Medical Oncology at Dana-Farber Cancer Institute in Boston and senior author of the study. "Now, we’ve found that it also plays a role in the skin’s tanning response to the sun’s ultraviolet radiation—a nearly constant environmental exposure."
The researchers also found evidence that the same essential process underlies other instances of skin darkening, including age spots and the spots that sometimes occur during pregnancy or as a side effect of certain medications, Fisher said.
The Dana-Farber researchers had already demonstrated that, rather than the pigment-producing melanocytes, the more abundant and superficial keratinocytes react to sun exposure. "It makes sense that you would want the most superficial cells to act as UV sensors," Fisher said of his earlier discovery.
When keratinocytes are exposed to the sun’s rays, they produce melanocyte-stimulating hormone (MSH). MSH triggers receptors found on the surface of melanocytes, causing them to manufacture the skin-bronzing pigment.
Differences among people in their ability to tan stem from variation among them in the MSH receptor, he explained. For example, the receptor variant found in redheads doesn’t respond to MSH, leaving them unable to get a tan in the natural way.
However, the researchers hadn’t identified the factors responsible for turning on the pigment-stimulating hormone’s production in the first place.
They’ve now traced the process back to p53, a transcription factor that controls the activity of other genes and that is involved in many stress-related responses. Indeed, they showed, p53 directly stimulates the activity of the MSH-producing gene in response to UV radiation.
MSH is one product of a larger gene sequence that also encodes the natural morphine-like substance, called ß-endorphin, among other peptides, Fisher explained. While MSH drives the suntan response, ß-endorphin is believed to drive sun-seeking behavior and may act as a natural painkiller.
Fisher’s team further found that the ears and tails of mice lacking p53 lose the ability to tan. Similarly, the induction of ß-endorphin by UV also depends on p53.
"The induction of ß-endorphin appears to be hard-wired to the tanning pathway," Fisher said. "This might explain addictive behaviors associated with sun-seeking or the use of tanning salons."
The researchers found evidence that similar events to those seen in the mice also occur in human skin. They showed that p53 is rapidly induced in virtually every keratinocyte of human skin samples within an hour of UV exposure, followed by the induction of MSH and a transcription factor that governs the production of pigment by melanocytes.
The findings led the researchers to consider that p53 could be involved in other instances of skin pigmentation not associated with the sun. For instance, some chemotherapy drugs can cause the skin to become "hyperpigmented," as observed by Fisher’s team.
"We know that p53 is induced by many types of stress," he said. Therefore, they reasoned, other types of stress—due to age, pregnancy, drugs or other factors—might produce a reaction that "mimics" the suntan response. Indeed, they found that a drug known to stimulate p53 darkened the skin of normal mice but not the skin of mice lacking p53.
To further explore the connection between p53 and other forms of skin pigmentation, the researchers examined human basal cell carcinomas, one of the most common forms of skin cancer. The cancer is pigmented in some patients, but not others, they knew. In every case they found that the pigmented cancers harbored a normal p53 gene, while the nonpigmented samples harbored a mutated version of the gene.
"Certain drugs are probably inadvertently activating p53 and, with it, the sun tanning pathway," Fisher speculated. "We might now be able to find ways to interfere with this process to prevent it from occurring."
By the same token, a more complete understanding of the suntan process could lead to products that can produce a tan safely without exposure to potentially damaging UV radiation—even in those people who otherwise don’t tan. Fisher said he is involved in a small biotechnology company that is working to develop such a product.
Erin Doonan | EurekAlert!
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