CURRENT CONCEPTS IN NEUROONCOLOGY - THE CELL-CYCLE - A REVIEW

UNCONTROLLED CELLULAR PROLIFERATION is the hallmark of human malignant brain tumors. Their growth proceeds inexorably, in part because their cellular constituents have an altered genetic code that enables them to evade the checks and balances of the normal cell cycle. Recently, a number of major advances in molecular biology have led to the identif ication of several critical genetic and enzymatic pathways that are di sturbed in cancer cells resulting in uncontrolled cell cycling. We now know that the progression of a cell through the cell cycle is control led in part by a series of protein kinases, the activity of which is r egulated by a group of proteins called cyclins. Cyclins act in concert with the cyclin-dependent kinases (CDKs) to phosphorylate key substra tes that facilitate the passage of the cell through each phase of the cell cycle. A critical target of cyclin-CDK enzymes is the retinoblast oma tumor suppressor protein, and phosphorylation of this protein inhi bits its ability to restrain activity of a family of transcription fac tors (E2F family), which induce expression of genes important for cell proliferation, In addition to the cyclins and CDKs, there is an emerg ing family of CDK inhibitors, which modulate the activity of cyclins a nd CDKs. CDK inhibitors inhibit cyclin CDK complexes and transduce int ernal or external growth-suppressive signals, which act on the cell cy cle machinery. Accordingly, all CDK inhibitors are candidate tumor sup pressor genes. It is becoming clear that a common feature of cancer ce lls is the abrogation of cell cycle checkpoints, either by aberrant ex pression of positive regulators (for example, cyclins and CDKs) or the loss of negative regulators, including p21(Cip 1) through loss of fun ction of its transcriptional activator p53, or deletion or mutation of p16(INK4A) (multiple tumor suppressor 1/CDKN2) and the retinoblastoma tumor suppressor protein. in this review, we describe in detail our c urrent knowledge of the normal cell cycle and how it is disturbed in c ancer cells. Because there have now been a number of recent studies sh owing alterations in cell cycle gene expression in human brain tumors, we wilt review the derangements in both the positive and negative cel l cycle regulators that have been reported for these neoplasms. A thor ough understanding of the molecular events of the cell cycle may lead to new opportunities by which astrocytoma cell proliferation can be co ntrolled either pharmacologically or by gene transfer techniques.