Human melanocyte senescence and melanoma susceptibility genes

Abstract

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 cyclindependent 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.

Pirin Inhibits Cellular Senescence in Melanocytic Cells

“…This anticancer barrier is of particular relevance in melanoma, which often stems from a nevus that is composed of senescent melanocytes. 3 One could, therefore, hypothesize that the decrease in PIR levels that characterizes the transition from normal melanocytes to nevi is associated with the onset of cellular senescence. In accordance with this view, PIR expression in intradermal nevi is restricted to the superficial portion of the lesion, whereas deeper parts, which are rich in senescent cells, do not express PIR (data not shown).…”

“…1,2 The specific molecular circuitry underlying the onset of cellular senescence is dependent on the type of stimulus and on the cellular context. A central role is held by the activation of the tumor suppressor proteins p53 and retinoblastoma susceptibility protein (pRB), [3][4][5] which act by interfering with the transcriptional program of the cell and ultimately arresting cell cycle progression.…”

“…9 In fact, many of the melanoma-associated tumor suppressor genes identified to date are themselves involved in control of senescence, including BRAF (encoding serine/threonine-protein kinase B-raf), CKD4 (cyclin-dependent kinase 4), and CDKN2A (encoding cyclin-dependent kinase inhibitor 2A isoforms p16 INK4a and p19 ARF ). 3,10 Nevi frequently harbor oncogenic mutations of the tyrosine kinase BRAF gene, particularly V600E, 11 and BRAF V600E is also found in approximately 70% of cutaneous melanomas. 12 Expression of BRAF V600E in human melanocytes leads to oncogene-induced senescence, 8 which can be considered as a mechanism that protects from malignant progression.…”

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

“…p16 is itself a tumour suppressor; germline mutations at its locus CDKN2A are principally associated with familial melanoma in humans, with some increased incidence of pancreatic cancer, suggesting particular importance in melanocytes (Gruis et al, 1995;Bennett, 2003;Hayward, 2003;Kefford et al, 2004;Gray-Schopfer and Bennett, 2006). In sporadic cancers, p16 alterations and deletions are more broadly distributed, being found in many types of cancer.…”

“…Humans carrying p16 mutations have not only increased susceptibility to melanoma, but usually also numerous melanocytic naevi (moles), often large (Gruis et al, 1995;Bennett and Medrano, 2002;Bennett, 2003), implying a role for p16 in limiting naevus growth in these families. This led to surmises that moles may be melanocyte clones that have proliferated following a first mutation, then senesced (Bennett and Medrano, 2002;Mooi and Peeper, 2002;Bastian, 2003).…”