Abnormal cell cycle regulation in malignancy

The cell cycle consists of an initial growth phase (G(1)), DNA replication (S), a gap phase (G(2)), and mitosis (M), after which the cell may differen tiate or enter the resting state (G(0)). The cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation eve nts, involving protein kinases, protein phosphatases, cyclins, cyclin-depen dent kinases, and cyclin-dependent kinase inhibitors, that ultimately impin ge on the activity of transcription factors. Unreplicated or damaged DNA bl ocks the progression of the cell cycle at checkpoints, including a late G(1 ) checkpoint regulated by the dephosphorylated retinoblastoma protein and a late G(2) checkpoint regulated by the phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell cycle regulator genes may be co nsidered protooncogenes or tumor suppressor genes, and point mutations, amp lifications, deletions, or rearrangements involving their loci, particularl y those in the "RB pathway," are associated with various tumors. A number o f molecular techniques may be used to detect genomic alterations or posttra nscriptional modifications, but immunohistochemistry remains the most commo n method to determine expression levels of a regulatory protein. Multivaria te analysis of the usefulness in prognosis has been applied most often for the general proliferation antigen Ki-67.