The retinoblastoma protein, the cell cycle, and melanoma

The retinoblastoma-associated protein (pRB) is central to a cellular mechanism that governs the commitment of a cell to divide. When functioning normally, it integrates growth stimulatory and growth inhibitory signals that arise from both within the cell itself and from its immediate environment, and if proliferation is inappropriate in the prevailing conditions, it binds key transcription factors, and thereby prevents them from initiating the transcription of genes whose products are critical for entry into the DNA-synthetic S-phase of the cell cycle. If the conditions are such that division is required, pRB releases the transcription factors, the target genes are expressed, and the cell cycle proceeds. When this system fails, cellular proliferation can occur when it should not, a hallmark of cancer.

The change of state of pRB from being growth repressive to being growth permissive is governed principally by changes of phosphorylation, something controlled primarily by cyclin-dependent kinases (CDKs). These, as their name suggests, are regulated by cyclins, which may be induced by the presence of extracellular mitogens, linking the extracellular context to the pRB mechanism. Also important are inhibitors of these CDKs, called CKIs, as they can "veto" CDK phosphorylation of pRB if internal or external factors so dictate. It is a complex but well-ordered molecular system that provides sensitivity to a range of possibly conflicting simultaneous stimuli culminating in an irreversible one-time licence to replicate the genome, an essential prerequisite to cell division and proliferation.

The study of hereditary melanoma predisposition syndromes has revealed that in one, the CDKN2A gene, encoding the p16 CKI, is defective, while in another, the CDK4 gene is mutated, and CDK4 is a major kinase for pRB inhibited by p16. Survivors of childhood hereditary retinoblastoma, where the gene encoding pRB is involved, also develop melanoma with higher than normal frequency. These suggest that the pRB system is particularly important in the prevention of melanoma, something supported by the very frequent finding of mutation or loss of protein expression of these components in sporadic melanoma.