Contrasting roles of NF-kappaB and JNK in arsenite-induced p53-independent expression of GADD45alpha

Oncogene. 2001 Jun 14;20(27):3585-9. doi: 10.1038/sj.onc.1204442.

Abstract

Growth arrest and DNA damage-inducible protein 45alpha (GADD45alpha) is an important cell cycle checkpoint protein that arrests cells at G2/M phase by inhibiting the activity of G2-specific kinase, cyclin B/p34cdc2. We report here that arsenite induces GADD45alpha expression in a p53-independent fashion and that this GADD45alpha induction by arsenite is regulated by NF-kappaB and c-Jun-N-terminal kinase (JNK) oppositely. In human bronchial epithelial cells overexpressing a kinase-mutated form of IkappaB kinase beta (IKKbeta-KM), the activation of NF-kappaB was inhibited. However, the G2/M cell cycle arrest and expression of GADD45alpha was substantially enhanced in response to arsenite in these cells. Expression of a dominant-negative mutant of SEK1 that blocks JNK activation decreased arsenite-induced GADD45alpha expression. Analysis of GADD45alpha expression in both wild-type and p53-/- fibroblasts indicated that the induction of GADD45alpha by arsenite was independent of the status of p53 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arsenites / pharmacology*
  • Bronchi / cytology
  • Bronchi / physiology
  • Cell Cycle / physiology*
  • Cell Line
  • DNA Damage*
  • Enzyme Activation
  • Fibroblasts / physiology
  • G2 Phase
  • GADD45 Proteins
  • Gene Expression Regulation / drug effects*
  • Genes, p53
  • Humans
  • I-kappa B Kinase
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Kinetics
  • MAP Kinase Kinase 4*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mitosis
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / genetics*
  • Recombinant Proteins / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / physiology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Arsenites
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Proteins
  • Recombinant Proteins
  • Tumor Suppressor Protein p53
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • arsenite