Enhanced G2-M arrest by nuclear factor-{kappa}B-dependent p21waf1/cip1 induction

Mol Cancer Res. 2005 Jun;3(6):345-53. doi: 10.1158/1541-7786.MCR-05-0028.

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates cell survival pathways, but the molecular mechanisms involved are not completely understood. Here, we developed a NF-kappaB reporter cell system derived from CEM T leukemic cells to monitor the consequences of NF-kappaB activation following DNA damage insults. Cells that activated NF-kappaB in response to ionizing radiation or etoposide arrested in the G2-M phase for a prolonged time, which was followed by increased cell cycle reentry and survival. In contrast, those that failed to activate NF-kappaB underwent transient G2-M arrest and extensive cell death. Importantly, p21waf1/cip1 was induced in S-G2-M phases in a NF-kappaB-dependent manner, and RNA interference of this cell cycle regulator reduced the observed NF-kappaB-dependent phenotypes. Thus, cell cycle-coupled induction of p21waf1/cip1 by NF-kappaB represents a resistance mechanism in certain cancer cells.

Publication types

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

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Camptothecin / pharmacology
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p21
  • Doxorubicin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Etoposide / pharmacology
  • Female
  • Flow Cytometry
  • G2 Phase*
  • Humans
  • Mitosis*
  • NF-kappa B / metabolism*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • RNA Interference
  • Radiation, Ionizing
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / radiation effects
  • Time Factors
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antibiotics, Antineoplastic
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • NF-kappa B
  • Nucleic Acid Synthesis Inhibitors
  • Tumor Necrosis Factor-alpha
  • Etoposide
  • Doxorubicin
  • Camptothecin