Human melanocyte senescence and melanoma susceptibility genes.
The molecular mechanisms and biology of cellular senescence in human melanocytes are discussed, including similarities to and differences from senescence in fibroblasts and other cell lineages. Special reference is made to the fact that the known melanoma susceptibility genes in the human, Inhibitor A of [cyclin-dependent] kinase 4-alternative reading frame (INK4A-ARF) and cyclin-dependent kinase 4, are involved in the regulation of cellular senescence, and possible reasons why this should be so. Based on the evidence including growth and survival kinetics of human and mouse melanocytes carrying germline deficiencies in the INK4A sequence, it is suggested that an 'M0' or p16/RB-dependent form of senescence may be particularly important in melanocytes. A speculative model is proposed, relating current concepts of early melanoma progression to the processes of cellular senescence and immortalization. This includes the suggestion that moles or nevi are senescent clones of melanocytes.
Bennett
Dorothy C
DC
Department of Basic Medical Sciences, St George's Hospital Medical School, London SW17 0RE, UK. dbennett@sghms.ac.uk
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D018450:Disease Progression; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000502:physiology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases