Well-known protein may play unexpected role

May 01, 2007, 4:00am

The sensor and effector at the beginning of the tanning pathway within keratinocytes is the normal p53 protein, according to a new study. A better understanding of how this protein operates may open the door to better skin cancer prognostic and treatment discoveries.

Key Points

Boston - A new study sheds light on the pathway through which ultraviolet radiation regulates skin pigmentation - colloquially known as tanning.

"What basically came from the study were the observations that the sensor and effector at the very beginning of the tanning pathway within keratinocytes is the normal p53 protein," says the study's senior author, David E. Fisher, M.D., Ph.D., oncologist, director of the melanoma program at the Dana Farber Cancer Institute Medical School, Boston.

"What we knew was that the level of upregulation for MSH involves transcription of the MSH gene. We knew that suddenly this gene becomes very active. So, we were able to use a series of molecular tools to identify the exact region of that gene that was changing in response to UV. When we did this, we suddenly realized that the regulatory event would be controlled by the p53 protein," Dr. Fisher tells Dermatology Times.

Protein surprises

The observation was striking, Dr. Fisher says, given that the well-known p53 protein had never been linked to something as mundane as a person exposing himself or herself to the sun and getting a tan.

Rather, scientists have, until now, thought of p53 as a tumor suppressor gene. Inactivation of p53 commonly accompanies the progression of early tumorigenic lesions.

"So, what we were looking at here was the role of p53 in a normal physiologic setting," he says.

Implications from recognizing p53's role in the normal tanning pathway are many, the researcher says.

One example: Oncology studies have shown that p53 is a stress protein that responds to diverse types of stress. This study suggests that skin exposure to diverse types of stress (independent of UV) might also upregulate p53, triggering the pigmentation response.

"We suspect that many dermatologic instances of benign hyperpigmentation that occur in a significant fraction of the population might be occurring as a consequence of the fact that there is inadvertent activation of p53 by some stress that was inflicted on the skin, such as chronic infection, trauma, an inflammatory response, use of topical drugs as a side effect," Dr. Fisher says. "We suspect that because p53 is so ubiquitous in its ability to respond to different types of stress that this suggests a linkage between the normal tanning pathway and abnormal or pathologic hyperpigmentation, which is extremely common."

Portal to greater understanding?

Researchers' better understanding of this pathway could open the door to the development of new drugs to treat hyperpigmentation.

"Current treatments target the enzyme tyrosinase, which is deep down in the melanocytes. What this would suggest is that there might be opportunities to interfere with hyperpigmentation much more superficially - at the level of keratinocytes," Dr. Fisher says.

The results of this study have piqued Dr. Fisher's and others' interest about how it relates to skin cancer risk in humans, he says.

"There is quite a correlation between ability or inability to tan and risk of developing melanoma and other skin cancers," Dr. Fisher says.

"In most cases, we do not understand where the barriers are to tanning in different populations of people. We now have an idea what the pathway is, and (we) should be in a position to scrutinize exactly where the blockages are in terms of being able to identify molecular tests that would accurately predict individuals' cancer risk."

Disclosure: Dr. Fisher is a consultant for Novartis Pharmaceuticals and a consultant and equity holder at Magen Biosciences.

For more information: Cui R, Widlund HR, Feige E, Lin JY, Wilensky Dl, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. March 9, 2007: 853-864.