Chemically Induced Premature Mitosis: Differential Response in Rodent and Human Cells and the Relationship to Cyclin B Synthesis and p34cdc2/ Cyclin B Complex Formation

• Published in: Proceedings of the National Academy of Sciences - PNAS 1991-08, Vol.88 (15), p.6843-6847
• Main Authors: Steinmann, Kathleen E., Belinsky, Glenn S., Lee, Daniel, Schlegel, Robert
• Format: Article
• Language: English
• Subjects: 2-Aminopurine - pharmacology; Adenine - analogs & derivatives; Adenine - pharmacology; Animals; Caffeine - pharmacology; CDC2 Protein Kinase - metabolism; Cell cycle; Cell Line; Cell lines; Cells; CHO cells; Cricetinae; Cricetulus; Cyclins; Cyclins - biosynthesis; Cyclins - metabolism; DNA replication; Ethers, Cyclic - pharmacology; Hamsters; HeLa cells; HeLa Cells - cytology; HeLa Cells - drug effects; HeLa Cells - metabolism; Humans; Interphase; Kinetics; Macromolecular Substances; Mice; Mitosis; Mitosis - drug effects; Mitosis - radiation effects; Okadaic Acid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.15.6843

Normal eukaryotic cells do not initiate mitosis until DNA replication has been completed. This requirement can be bypassed by exposing cells to certain chemicals. We report here that chemically induced premature mitosis is not readily achieved in all mammalian species. Although hamster cells underwent premature mitosis following treatment with caffeine, the protein phosphatase inhibitor okadaic acid, and the protein kinase inhibitors 2-aminopurine and 6-dimethylaminopurine, the mouse and human cells examined in this study displayed little or no response to any of these compounds. Differences in cell permeability or metabolism could not account for the species specificity of these drugs, because other biochemical and mitosis-promoting activities were apparent in human cells. Cell-type specificity can be explained, however, by the timing of cyclin B synthesis and p34cdc2/cyclin B complex formation during the cell cycle. Synthesis of cyclin B and formation of a p34cdc2/cyclin B complex, both of which are required for initiation of mitosis, were prevalent in hamster cells arrested in S phase but were absent or barely detectable in arrested human cells. In hamster cells, the hyperphosphorylated form of p34cdc2was complexed with cyclin B and underwent tyrosine dephosphorylation during caffeine-induced premature mitosis. These findings indicate that the onset of mitosis is regulated somewhat differently among mammalian cell types and that these differences affect the vulnerability of cells to drug-induced mitotic aberrations and cytogenetic damage.