|Protein Plays an Important Role in Increased
Skin Pigmentation That Can Help Protect Against Harmful UV Exposure
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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Medical Research Agency — includes 27 Institutes and
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Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
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