The Cell Cycle – Theory and Application to Cancer

R. Parwaresch; P. Rudolph

doi:10.1159/000218858

Parwaresch, R.; Rudolph, P.

1996-01-01 00:00:00

The division cycle of normal mammalian cells is governed by a highly coordinated network of interacting mechanisms that ensure a correct succession of the biochemical and biophysical events culminating in mitosis. A family of specific protein kinases, the Cdks, constitute the motor element of cell cycle progression. Their function is regulated at several levels: 1. association with a cyclin subunit situates their activity in different phases of the cell cycle; 2. sequential phosphorylation and dephosphorylation on specific amino acid residues is required for their final activation; 3. their activity can be modulated by complexing with members of the cyclin-dependent kinase inhibitor family (Cdkls). The latter function to a large extent as effectors of signals emitted by cell surface receptors or internal sensors of defective biochemical and biophysical states termed checkpoints. While the fate of cells is largely influenced by external factors throughout Gl phase, an intrinsic program becomes responsible for cell cycle progression after the passage of the ‘restriction point’ at the Gl/S boundary. This crucial transition is controlled by a checkpoint mechanism in which the concerted action of p53 and the retinoblastoma protein may induce either a cell cycle arrest or apoptosis in response to genomic damage. Several other checkpoint functions regulate the entry into mitosis by assessing the completion of DNA replication and correct chromosome attachment to the spindle apparatus. Finally, the number of possible cell divisions is predetermined by the number of small oligonucleotide repeats at the utmost chromosome ends, the telomeres. Checkpoint mechanisms can be disrupted by viral oncoproteins or gene mutations. Loss of their function is likely to result in genomic destabili-zation and gene amplification, which again may allow for chromosome aberrations and, as several connections link the genome to the cell cycle machinery, may permit unrestrained cell growth. The majority of the cell cycle-related proteins, however, do not qualify for monitoring the prolifer-ative activity or the tumor growth fraction. To date, only three proteins: p345 (Ki-67), pl70 (topoisomerase II-alpha), and p100 (S-phase protein) have been identified as selective indicators of cellular proliferation. The first two recognize all cell cycle phases except GO, whereas the latter is specifically expressed in S, G2, and M phase cells. Application of antibodies to these proteins in clinical pathology was found to be highly relevant for the prediction of tumor biology and clinical courses.

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The Cell Cycle – Theory and Application to Cancer

$The division cycle of normal mammalian cells is governed by a highly coordinated network of interacting mechanisms that ensure a correct succession of the biochemical and biophysical events culminating in mitosis. A family of specific protein kinases, the Cdks, constitute the motor element of cell cycle progression. Their function is regulated at several levels: 1. association with a cyclin subunit situates their activity in different phases of the cell cycle; 2. sequential phosphorylation and dephosphorylation on specific amino acid residues is required for their final activation; 3. their activity can be modulated by complexing with members of the cyclin-dependent kinase inhibitor family (Cdkls). The latter function to a large extent as effectors of signals emitted by cell surface receptors or internal sensors of defective biochemical and biophysical states termed checkpoints. While the fate of cells is largely influenced by external factors throughout Gl phase, an intrinsic program becomes responsible for cell cycle progression after the passage of the ‘restriction point’ at the Gl/S boundary. This crucial transition is controlled by a checkpoint mechanism in which the concerted action of p53 and the retinoblastoma protein may induce either a cell cycle arrest or apoptosis in response to genomic damage. Several other checkpoint functions regulate the entry into mitosis by assessing the completion of DNA replication and correct chromosome attachment to the spindle apparatus. Finally, the number of possible cell divisions is predetermined by the number of small oligonucleotide repeats at the utmost chromosome ends, the telomeres. Checkpoint mechanisms can be disrupted by viral oncoproteins or gene mutations. Loss of their function is likely to result in genomic destabili-zation and gene amplification, which again may allow for chromosome aberrations and, as several connections link the genome to the cell cycle machinery, may permit unrestrained cell growth. The majority of the cell cycle-related proteins, however, do not qualify for monitoring the prolifer-ative activity or the tumor growth fraction. To date, only three proteins: p345 (Ki-67), pl70 (topoisomerase II-alpha), and p100 (S-phase protein) have been identified as selective indicators of cellular proliferation. The first two recognize all cell cycle phases except GO, whereas the latter is specifically expressed in S, G2, and M phase cells. Application of antibodies to these proteins in clinical pathology was found to be highly relevant for the prediction of tumor biology and clinical courses.$

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The Cell Cycle – Theory and Application to Cancer

The Cell Cycle – Theory and Application to Cancer

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The Cell Cycle – Theory and Application to Cancer

The Cell Cycle – Theory and Application to Cancer

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