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Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 | T Waldman
; C Lengauer
; K W Kinzler
; B Vogelstein
; | Date: |
20 Jun 1996 | Journal: | Nature, 381 (6584), 713-6 | Abstract: | Precise coordination of the S and M phases of the eukaryotic cell cycle is critical not only for normal cell division, but also for effective growth arrest under conditions of stress. When damaged, a cell must communicate signals to both the mitotic and DNA synthesis machineries so that a mitotic block is not followed by an extra S phase, or vice versa. The biochemical mechanisms regulating this coordination, termed checkpoints, have been identified in lower eukaryotes, but are largely unknown in mammalian cells. Here we show that p21 WAF1/CIP1, the prototype inhibitor of cyclin-dependent kinases (CDKs), is required for this coordination in human cells. In the absence of p21, DNA-damaged cells arrest in a G2-like state, but then undergo additional S phases without intervening normal mitoses. They thereby acquire grossly deformed, polyploid nuclei and subsequently die through apoptosis. Perhaps not by coincidence, the DNA-damaging agents that can cause S/M uncoupling are used in the clinic to kill cancer cells preferentially. | Source: | PubMed, pmid8649519 doi: 10.1038/381713a0 | Services: | Forum | Review | Favorites |
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