Melanomas, from the cell cycle point of view (Review)

Transformation of melanocytes to metastatic melanoma cells is characterized by unrestricted proliferation under growth-factor-deprived conditions, genetic loss of cyclin dependent kinase (CDK) inhibitors (CKI, e.g. p16INK4A), and aberrant production of autocrine growth factors (e.g. basic fibroblast growth factor). The latter induces increased expression of positive CDK regulators (e.g. cyclin D1) and reduced expression of additional CKIs (e.g. p27KIP1). Combined, these events lead to sustained CDK activity and hyperphosphorylation/inactivation of the retinoblastoma tumor suppressor protein (Rb). The persistent Rb phosphorylation causes the accumulation of E2F and the transcription of its target genes whose products promote cell cycle progression.