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Aging, The Molecular Concepts


Progression through the cell cycle is exquisitely regulated by proteins known as cyclin-dependent kinases, inhibitors of these kinases (CDK-1), of which several have been identified (p21Waf-l/SDI-l, p27Kip-l, p57, pl6INK4 and pl5), and transcription factors. Eumelanin accumulation correlates with increased expression of the Cdk-1 p27Kip1, poor or absent Cdk-2 activity, increased binding of the Cdk-1 pl6 to Cdk4 and a modest increase in p21SDI-1/Waf-1 (19).

The E2F family of transcription factors consists of six distinct E2F members and at least two heterodimer partners, DPI and DP2. The individual family members are able to form a variety of protein complexes and may play distinct roles in proliferation, cell cycle exit and terminal differentiation. E2F4 and E2F5 form complexes with the p107 and p130 retinoblastoma family proteins and function as transcriptional repressers in quiescent cells (20). In particular, E2F-p130 complexes may repress E2F1 and E2F2 genes by binding to E2F DNA-binding elements in their own promoters. We have found that accumulation of high levels of brown/black melanin (eumelanin), after treatment with cAMP inducers, results in reduced or absent E2F-1 and E2F2 protein expression, increased levels of E2F5 protein and cell cycle exit (2). However, after the same treatment, melanocytes cultured from light skin do not downregulate E2F1 or E2F2 protein levels. These melanocytes are able to proliferate for >10 weeks in the presence of cholera toxin or α-MSH (2). MITF can associate, at least in vitro, to the retinoblastoma protein pRB. In addition, MITF could potentially be involved in regulating E2F2 expression. A consensus E-box, needed for c-myc binding and transcription of E2F2 (21), overlaps with a CATGTG M-box in the human E2F2 promoter. MITF could compete with c-myc for binding to the E-box resulting in decreased levels of E2F2 transcription and consequently reduced E2F2 protein levels. Thus, it is possible that, in addition to its activity as a melanogenic transcription factor, MITF could also be involved in regulating the melanocyte's cell cycle.

Mammalian pigmentation is a very complex pathway, which involves multiple levels of regulation by multiple players. It was shown, the importance and intricacy of the cAMP pathway in regulating the melanocyte cell cycle. It has been identified three members of the E2F family: E2F1, E2F2 and E2F5 and the Cdk-Is p27 and p16 as important players in the regulation of the melanocyte cell cycle.

However, it may be too naive to postulate that these proteins are the only factors involved in terminal differentiation of the melanocyte. It was proposed that terminal differentiation is a tumor suppressor mechanism only partially operative under imperfect eumelanization. The model described above could explain the dissimilar changes in pigmentation observed with aging in Caucasian individuals, particularly in areas of the skin that have been exposed to the environment throughout time. It is not at present known whether a similar pathway operates in vivo. However, heterogeneity in skin pigmentation and, in particular, the presence of lentigo senilis and increased frequency of melanomas with aging, in individuals from light skin backgrounds, suggest that this might be the case.

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