MELANOMAS, FROM THE CELL-CYCLE POINT-OF-VIEW (REVIEW)

Transformation of melanocytes to metastatic melanoma cells is characte rized by unrestricted proliferation under growth-factor-deprived condi tions, genetic loss of cyclin dependent kinase (CDK) inhibitors (CKI, e.g. p16(INK4A)), and aberrant production of autocrine growth factors (e.g. basic fibroblast growth factor). The latter induces increased ex pression of positive CDK regulators (e.g. cyclin D1) and reduced expre ssion of additional CKIs (e.g. p27(KIP1)). Combined, these events lead to sustained CDK activity and hyperphosphorylation/inactivation of th e retinoblastoma tumor suppressor protein (Rb). The persistent Rb phos phorylation causes the accumulation of E2F and the transcription of it s target genes whose products promote cell cycle progression.