Norman Sharpless

Mechanisms of stem cell senescence; genetics of the INK4/ARF tumor suppressor locus in melanoma; melanoma therapeutics

Institution:  University of North Carolina School of Medicine

Website:  http://cancer.med.unc.edu/research/faculty/displayMember.asp?ID=274

Email:  norman_sharpless@med.unc.edu

Voice:  (919) 966-1185

Publications

The lab relies on murine genetic approaches to study the roles of the INK4/ARF tumor suppressor locus in human cancer and aging. At present, the lab has two main focuses: Stem Cell Aging:Cancer and degenerative diseases are much more common in old people than young. Although this has been well-recognized in clinical medicine for decades, scientists do not agree as to why this occurs. Recently, work from several labs including our own has shown that humans age, in part, because important regenerative cells lose their capacity to divide with the passage of time. That is, the tissues and organs from old people are less able to replace and regenerate lost or damaged cells than the corresponding tissues and organs from young people. Our lab has studied mechanisms that underlie this age-dependent failure of cell division; in fact, we have shown the surprising result that cellular programs that function to prevent cancer untowardly also affect aging. Specifically, cellular “senescence” is now believed to be of major importance in the process of aging. Senescence refers to a permanent growth arrest induced in formerly dividing cells by the activation of genes that prevent cancer. The good news in this system is that the normal functioning of these ‘tumor suppressor genes’ prevents cancer; the bad news is that these same genetic events appear to cause aging by activating cellular senescence. Melanoma and Murine Models of Cancer: Because of the important role of p16INK4a in preventing melanoma, the lab has long been interested in this particularly deadly form of skin cancer. Specifically, we are interested in using genetically engineered models of cancer to study melanoma genetics. We have shown a role for the p16INK4a-RB and ARF-p53 tumor suppressor pathways in repressing this important human cancer in response to RAS-RAF activation. We have generated highly faithful models of human melanoma, and have used these to study novel therapeutics. We have also discovered a novel human melanoma sub-type based on expression profiling, and have identified a new therapeutic target (CD200) for treatment of melanoma.