Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21

Todd Waldman, Christoph Lengauer, Kenneth W Kinzler, Bert Vogelstein

Research output: Contribution to journalArticle

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 proto-type inhibitor of cyclin-dependent kinases (CDKs)4, 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.

Original languageEnglish (US)
Pages (from-to)713-716
Number of pages4
JournalNature
Volume381
Issue number6584
DOIs
StatePublished - 1996

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S Phase
Mitosis
Antineoplastic Agents
Cell Division
DNA
Cyclin-Dependent Kinase 4
Polyploidy
Eukaryotic Cells
Eukaryota
Cell Cycle
Apoptosis
Growth
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. / Waldman, Todd; Lengauer, Christoph; Kinzler, Kenneth W; Vogelstein, Bert.

In: Nature, Vol. 381, No. 6584, 1996, p. 713-716.

Research output: Contribution to journalArticle

Waldman, Todd ; Lengauer, Christoph ; Kinzler, Kenneth W ; Vogelstein, Bert. / Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. In: Nature. 1996 ; Vol. 381, No. 6584. pp. 713-716.
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