Cell division cycle alterations in human malignancies

his paper briefly reviews studies on the genes that control the cell division process in human cancerogenesis. It describes the key biochemical events of the division cycle, their regulation, and genetic alterations that occur in human malignancies. The process of cell division is the result of a cycling and time-regulated activation of specific enzymes that phosphorylate (and thus control) proteins required for progression toward cell mitosis. These enzymes, named cyclin-dependent kinases (CDKs), are activated by the binding of protein co-factors (i.e. cyclins) and are inhibited by specific proteins (CDK-inhibitors or CDIs). A large body of evidence demonstrates that several genes involved in cell cycle control are altered in human tumors. These include, in addition to the two archetypal tumor suppressor genes RB and p53, a CDK gene (CDK4), a cyclin gene (CCDN1) and a CDI gene (p16(INK4A)). In particular, p16(INK4A) gene is inactivated in many different malignancies with sometimes a greater than 80% incidence. These observations, along with studies carried out in animal models, suggest that almost all human cancers show alterations of the molecular mechanisms that control the division cycle. Such alterations might allow somatic cells to escape physiological cellular differentiation and senescence, thus favouring the development of further genetic aberrations and the progression towards an invasive malignant phenotype. In conclusion, we shall envisage possible scenarios for future clinical research (including potential diagnostic developments and new therapeutical strategies) that are related to the above biochemical investigations.