Uncoupling of S Phase and Mitosis Induced by Anticancer Agents in Cells Lacking p21

Nature. 1996 Jun 20;381(6584):713-6. doi: 10.1038/381713a0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Bisbenzimidazole
  • Camptothecin / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclins / physiology*
  • DNA Damage
  • Doxorubicin / pharmacology
  • Enzyme Inhibitors*
  • Etoposide / pharmacology
  • Fluorescent Dyes
  • Gamma Rays
  • Humans
  • Mitosis / drug effects
  • Mitosis / physiology*
  • S Phase / drug effects
  • S Phase / physiology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Etoposide
  • Doxorubicin
  • Cyclin-Dependent Kinases
  • Bisbenzimidazole
  • Camptothecin