Researchers have identified a protein that plays an important, early role in the increase of protective skin pigmentation after exposure to ultraviolet (UV) radiation. The protein, called SOX9, is a transcription factor known to participate in embryo development and to be expressed in many adult tissues including the heart, kidney, and brain. Transcription factors control when and where genes (and hence the proteins encoded by those genes) are expressed. This study, led by investigators in the National Cancer Institute (NCI), part of the National Institutes of Health, confirms the importance of SOX9 to adult skin cells and is the first to show that a protein in the SOX family can be regulated by UV radiation. The results appear in the August 13, 2007, Proceedings of the National Academy of Sciences.

Melanin is a pigment produced in the skin that helps protect cells from cancer-causing UV rays. Specialized cells called melanocytes produce the melanin, which is then transported to other epidermal cells (called keratinocytes) that make up the majority of the skin. Melanoma, a cancer of melanocytes, is the most deadly of the skin cancers, and its incidence is rising in the United States.

UV radiation from the sun or other sources, such as tanning parlors, can cause many types of damage to the skin and has been associated with a process that leads to many types of skin cancers. Individuals with lighter skin incur greater damage from UV and thus have significantly higher risk for skin cancer.

“Increased pigmentation of the skin from UV is thought to help minimize the damage from UV,” said NCI Director John E. Niederhuber, M.D. “This research on SOX9 not only gives us important insights into the intricate mechanism our body uses to protect itself from ultraviolet rays, but also into cellular pathways that might contribute to the origins and spread of melanoma.”

After showing that melanocytes in normal human skin express SOX9 under normal conditions, the investigators exposed normal human melanocytes to UV radiation, and compared the levels of SOX9 between radiated and non-radiated cells. They found that levels of SOX9 increased within two hours after UV exposure, and continued to increase until eight hours after exposure.

The investigators next attempted to pinpoint the cellular mechanisms responsible for the increased levels of SOX9 after UV exposure. They chose to examine a cell-signaling pathway, called the cAMP pathway, that is known contribute to the regulation of human pigmentation and mediate the production of melanin. The researchers exposed normal human melanocytes and reconstructed skin samples to a chemical called forskolin, which stimulates the cAMP pathway. They also exposed another set of cells and skin samples to UV radiation.

Both treatments led to increased levels of SOX9. However, those increases could be prevented by a cAMP inhibitor, indicating that the cAMP pathway plays a critical role in the increased levels of SOX9 after UV exposure. When the investigators exposed normal human melanocytes to a protein called ASP, which inhibits the formation of melanin, the levels of SOX9 declined.

The researchers next tested whether SOX9 could activate several genes involved in melanin production. They showed that over-expression of SOX9 directly activated the promoters (the part of a gene containing information to turn the gene off or on) of two important pigment-related genes, called MITF and DCT. Both genes regulate pigment production in normal melanocytes. Knowing which other genes may be involved in pigment production will be important for future research efforts.

“The most novel part of this study was the fact that we identified a new transcription factor that may be the earliest responder to stimulation of pigmentation such as seen in the tanning reaction following UV exposure,” said Vincent Hearing, Ph.D., chief of the NCI’s Center for Cancer Research’s (CCR) Pigment Cell Biology Section and senior author of the study. “SOX9 is likely one of the first factors that’s activated to start the chain of events that eventually leads to increases in skin pigmentation.”

Hearing’s laboratory is now examining the effect of SOX9 on the proliferation and the tumor-promoting properties of melanoma cells, to see whether SOX9 could be used to target melanoma via SOX9.

Researchers are from the Pigment Cell Biology Section, Laboratory of Cell Biology, CCR, NCI, Bethesda, Md.; and from the Université de Nice, Nice, France. For more information on this area of research and on the Laboratory of Cell Biology, go to http://ccr.cancer.gov.

For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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