p16INK4A and Familial Melanoma

Cell division is controlled by a group of positive and negative regulatory molecules that act at experimentally defined phases throughout the cell-division cycle. Perturbations in these critical phases contribute to tumor development by allowing uncontrolled cell proliferation. During the cell-division cycle, cells in transit pass from a stage termed G1 to the DNA synthesis (or S) phase. At G1 phase, cells continue to synthesize RNA and proteins and irrevocably commit to DNA synthesis. This phase is controlled by several protein complexes including those consisting of cyclin-dependent kinases (CDK4 and CDK6) and cyclin D. These complexes are inhibited by the INK4 family of proteins—p16^INK4A , p15^INK4B , p18^INK4C , and p19^INK4D . Genetic alterations affecting p16^INK4A and cyclin D1 are so frequent in human cancers that inactivation of these proteins is believed to be necessary for tumor development. Broadly applicable anticancer therapies might be based on restoration of p16^INK4A CDK inhibitory function.