The metal-responsive transcription factor-1 contributes to HIF-1 activation during hypoxic stress

Biochem Biophys Res Commun. 2005 Nov 25;337(3):860-7. doi: 10.1016/j.bbrc.2005.09.124. Epub 2005 Sep 29.

Abstract

Hypoxia-inducible factor-1 (HIF-1), the major transcriptional regulator of the mammalian cellular response to low oxygen (hypoxia), is embedded within a complex network of signaling pathways. We have been investigating the importance of another stress-responsive transcription factor, MTF-1, for the adaptation of cells to hypoxia. This article reports that MTF-1 plays a central role in hypoxic cells by contributing to HIF-1 activity. Loss of MTF-1 in transformed Mtf1 null mouse embryonic fibroblasts (MEFs) results in an attenuation of nuclear HIF-1alpha protein accumulation, HIF-1 transcriptional activity, and expression of an established HIF-1 target gene, glucose transporter-1 (Glut1). Mtf1 null (Mtf1 KO) MEFs also have constitutively higher levels of both glutathione (GSH) and the rate-limiting enzyme involved in GSH synthesis--glutamate cysteine ligase catalytic subunit--than wild type cells. The altered cellular redox state arising from increased GSH may perturb oxygen-sensing mechanisms in hypoxic Mtf1 KO cells and decrease the accumulation of HIF-1alpha protein. Together, these novel findings define a role for MTF-1 in the regulation of HIF-1 activity.

Publication types

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

MeSH terms

  • Animals
  • Cell Hypoxia / physiology
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / metabolism*
  • Glucose Transporter Type 1 / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Oxidative Stress / physiology*
  • Oxygen / metabolism
  • Signal Transduction / physiology
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Glucose Transporter Type 1
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Slc2a1 protein, mouse
  • Transcription Factors
  • transcription factor MTF-1
  • Oxygen