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A protein known as the "master watchman
of the genome" for its ability to guard against cancer-causing
DNA damage has been found to provide an entirely different
level of cancer protection: By prompting the skin to tan in
response to ultraviolet light from the sun, it deters the
development of melanoma skin cancer, the fastest-increasing
form of cancer in the world.
In a study in the journal Cell, researchers
at Dana-Farber Cancer Institute report that the protein, p53,
is not only linked to skin tanning, but also may play a role
in people's seemingly universal desire to be in the sun -
an activity that, by promoting tanning, can reduce one's risk
of melanoma.
"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 alpha-MSH, which attaches to nearby
skin cells called melanocytes and spurs them to produce skin-darkening
pigment called melanin. The chain of events within keratinocytes
that leads to alpha-MSH production, however, was a mystery.
Investigators knew that alpha-MSH is created
when another protein, known as pro-opiomelanocortin (or 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 alpha-MSH was
30 times above normal.
Further experiments clinched the case for
p53's role in tanning. When researchers inserted p53 into
keratinocytes, POMC levels rose dramatically. When they delivered
UV radiation to mice whose keratinocytes lacked p53, POMC
production was not induced and the mice did not tan.
The implications of the research go beyond
tanning. A common skin condition, especially among the elderly,
is the development of small, 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. 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,
or age spots - 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.
The same process that causes POMC to produce
alpha-MSH also leads to the production of b-endorphin, a protein
that binds to the body's opiate receptors and may be associated
with feelings of pleasure. "Even as p53 is causing 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 beta-endorphin is involved in sun-seeking behavior, which
often increases skin cancer risk."
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The study's lead author is Rutao Cui, MD,
PhD, of Dana-Farber and Children's Hospital. 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.
Dana-Farber
Cancer Institute 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.
Contact: Teresa Herbert
Dana-Farber Cancer
Institute
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