ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis

Curr Mol Med. 2009 May;9(4):411-6. doi: 10.2174/156652409788167096.

Abstract

Hypoxia/anoxia promotes tumor aggressiveness and negatively impacts tumor response to therapy. Coordinate regulation of HIF-dependent and HIF-independent pathways has been shown to contribute to cellular adaptation to hypoxic stress, and to couple macromolecular synthesis rates to reduced energy availability. An important component of this type of adaptation is the activation of the endoplasmic reticulum kinase PERK by acute or prolonged hypoxia. Activated PERK subsequently induces phosphorylation of the translation initiation factor eIF2alpha and translational upregulation of the transcription factor ATF4. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates amino acid metabolism, cellular redox state, and anti-stress responses. ATF4 expression can be regulated at transcriptional, translational, and post-translational levels. The functional activation of ATF4 under hypoxia and the overexpression of ATF4 in hypoxic areas of clinical samples of human tumors suggest that ATF4 plays a role in tumor hypoxic adaptation. Here we summarize recent findings regarding the regulation of ATF4 in transformed cells, clinical tumor samples and tumor models, and speculate on its potential role in tumor progression and chemoresistance.

Publication types

  • Review

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Hypoxia
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Neoplasms / etiology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Up-Regulation
  • eIF-2 Kinase / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Activating Transcription Factor 4
  • endothelial PAS domain-containing protein 1
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase