THE CELL-CYCLE - THEORY AND APPLICATION TO CANCER

The division cycle of normal mammalian cells is governed by a highly c oordinated network of interacting mechanisms that ensure a correct suc cession of the biochemical and biophysical events culminating in mitos is. A family of specific protein kinases, the Cdks, constitute the mot or element of cell cycle progression. Their function is regulated at s everal levels: 1. association with a cyclin subunit situates their act ivity in different phases of the cell cycle, 2. sequential phosphoryla tion and dephosphorylation on specific amino acid residues is required for their final activation; 3. their activity can be modulated by com plexing with members of the cyclin dependent kinase inhibitor family ( CdkIs). The latter function to a large extent as effecters of signals emitted by cell surface receptors or internal sensors of defective bio chemical and biophysical states termed check points. While the fate of cells is largely influenced by external factors throughout G1 phase, an intrinsic program becomes responsible for cell cycle progression af ter the passage of the 'restriction point' at the G1/S boundary. This crucial transition is controlled by a checkpoint mechanism in which th e concerted action of p53 and the retinoblastoma protein may induce ei ther a cell cycle arrest or apoptosis in response to genomic damage. S everal other checkpoint functions regulate the entry into mitosis by a ssessing the completion of DNA replication and correct chromosome atta chment to the spindle apparatus. Finally the number of possible cell d ivisions is predetermined by the number of small oligonucleotide repea ts at the utmost chromosome ends. the telomeres. Checkpoint mechanisms can be disrupted by viral oncoproteins or gene mutations. Loss of the ir function is likely to result in genomic destabilization and gene am plification, which again may allow for chromosome aberrations and, as several connections link the genome to the cell cycle machinery, may p ermit unrestrained cell growth. The majority of the cell cycle-related proteins? however, do not qualify for monitoring the proliferative ac tivity or the tumor growth fraction. To date, only three proteins: p34 5 (Ki-67), p170 (topoisomerase II-alpha), and p100 (S-phase protein) h ave been identified as selective indicators of cellular proliferation. The first two recognize all cell cycle phases except G0, whereas the latter is specifically expressed in S, G2, and M phase cells. Applicat ion of antibodies to these proteins in clinical pathology was found to be highly relevant for the prediction of tumor biology and clinical c ourses.