SUSTAINED ACCUMULATION OF THE MITOTIC CYCLINS AND TYROSINE-PHOSPHORYLATED P34(CDC2) IN HUMAN G(1)-S-ARRESTED CANCER-CELLS BUT NOT UNTRANSFORMED CELLS

Coupling mitosis to the completion of DNA replication in cycling embry onic extracts from Xenopus eggs appears to rely on blocking the activa tion of the tyrosine-phosphorylated p34(cdc2)/cyclin B, which continue s to build up when S phase is inhibited by adding unreplicated DNA (Sm ythe, C., and New-port, J. W., Cell, 68: 787-797, 1992). We show here that a similar mechanism might be operative in human tumor-derived cel ls, which, during a thymidine-aphidicolin block, stop progressing thro ugh S phase and thereby fail to undergo mitosis, Under such conditions , indeed, cancer cells do continue to accumulate cyclin A, cyclin B1, and tyrosine-phosphorylated p34(cdc2) to supranormal levels, a phenome non that does not occur in untransformed, nonimmortalized human fibrob lasts, Thus, in human cancer cells, the onset of active accumulation o f cyclin A and cyclin B1 can be uncoupled from transit through the G(1 )-S and S-G(2) borders, respectively, and, as in simple embryonic cell cycles, the coupling of mitosis to the completion of S phase presumab ly relies, at least in part, on the prevention of premature activation of the tyrosine-phosphorylated p34(cdc2)/cyclin B1 complex.