Aging in epidermal melanocytes: cell cycle genes and melanins.

With aging, melanocytes become unevenly distributed in the epidermis. In light skin individuals, hypopigmentation is found in association with focal hyperpigmentation (lentigo senilis). Apparently this results from progressive loss of active melanocytes and focal increase in melanocyte proliferation and/or aggregation. This paper summarizes the present knowledge on aging of melanocytes in vivo and in vitro, with a focus on the role of melanin as a determinant for proliferation and terminal differentiation. We describe that excessive melanin deposition by cyclic AMP-inducing agents results in increased expression of the cyclin-dependent kinase inhibitors p27Kp-1 and p21SDI-1/Waf-1, increased binding of p16 to CDK4, and terminal differentiation. Importantly, the efficiency with which the melanocytes exit the cell cycle depends on the melanin background of the donor's cells. Melanocytes from skin types IV-VI that accumulate large amounts of brown black melanin (eumelanin), lose expression of the transcription factors E2F1 and E2F2, two key regulatory proteins, and withdraw from the cell cycle more rapidly than melanocytes from skin types I and II that accumulate red/yellow melanin (pheomelanin). Thus, we propose that terminal differentiation is a tumor suppressor mechanism that becomes less efficient under imperfect eumelanization.