New insight into skin-tanning process suggests novel way of preventing skin cancer

Many scientists have theorized that tanning occurs when ultraviolet radiation strikes the nuclei of melanocytes, causing DNA damage that prompts the melanocytes to produce pigment. This supposition, however, conflicted with the results of Fisher's experiments. "Our work suggested that a peculiarity in the MC1R receptor on melanocytes is responsible for a failure to tan," Fisher relates. "But that sort of change on the cell surface shouldn't impede UV radiation from reaching the melanocyte's DNA."

If Fisher's results were correct, the traditional picture of the biology of tanning was wrong. In a series of experiments, Fisher's team found evidence to bolster their theory, leading to a new model of how tanning occurs.

The experiments demonstrated that, rather than acting directly on the nuclei of melanocytes, UV radiation acts on keratinocytes (the most abundant as well as superficial cells in the skin), causing them to produce and secrete MSH, which attaches to adjacent melanocytes and starts the pigment-making process.

While Fisher's model adequately explains why redheads don't tan, it isn't the only possibility. "Suppose that during the embryonic or fetal period MC1R never activated cAMP production in developing melanocytes," Fisher proposes. "Would mature melanocytes then be permanently 'crippled,' unable to respond to UV, regardless of how its signals were transmitted?"

One way to disprove that 'permanently crippled' scenario would be to see if melanocytes with abnormal MC1R receptors can be coaxed into producing pigment in adult mice. To attempt this, Fisher and his associates treated the skin of red-haired, fair-skinned mice with a compound known to increase cAMP levels. The compound, called forskolin, is derived from the root of the forskohlii plant found in India. The mice involved in the experiment turned dark, proving that melanocytes in redheads aren't inherently unable to make pigment if appropriately stimulated.

Further experiments showed that not only can red-haired mice be given tans without exposing them to UV light, but this sunless tanning process is virtually indistinguishable from that in dark-haired mice that tan naturally.

"When keratinocytes absorb melanin pigment, the pigment isn't randomly distributed within them," Fisher explains. "It forms arcs that look like tiny umbrellas over the keratinocyte's nucleus. When we artificially caused our red-haired mice to tan, the pigment in their keratinocytes made the exact same umbrella-like pattern."

The Dana-Farber researchers also showed that tans acquired through forskolin conferred significant protection against skin cancer caused by exposure to UV light. Fisher notes that while it is unknown whether forskolin will penetrate deeply enough in human skin to activate melanocytes, these results suggest that the search for other substances that do reach deep into the skin may well have the same pigmentation effects in people.

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