Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis

Cancer Biol Ther. 2005 Nov;4(11):1285-94. doi: 10.4161/cbt.4.11.2299. Epub 2005 Nov 7.

Abstract

HIF-1, a hypoxia inducible transcription factor, plays a pivotal role in the cellular response to hypoxia by activating genes involved in glucose metabolism, vascular remodeling, and erythropoiesis. We identified Mxi1, a c-Myc antagonist, as a novel target gene induced in hypoxia. Mxi1 was not induced in cells deficient in ARNT (HIF-1beta), suggesting that Mxi1 is a transcriptional target of the HIF-1 complex. Notably, c-Myc protein levels decreased during hypoxia but were stabilized by a proteasome inhibitor. Analysis of downstream transcriptional targets of c-Myc during hypoxia revealed that genes regulated by c-Myc, such as ornithine decarboxylase (ODC), were downregulated during hypoxia. In contrast, genes that are regulated by c-Myc and HIF-1, such as LDH-A, were upregulated. Mxi1 protects against c-Myc-dependent sensitization to hypoxia-induced apoptosis. The results suggest a coordinated mechanism for opposing c-Myc signaling during hypoxia that is mediated by a reduction in c-Myc levels, the induction of Mxi1, and a dominant effect of HIF-1 transcriptional activity.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Hypoxia / physiology*
  • Cell Line
  • Cell Line, Tumor
  • Cytoprotection / physiology*
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1 / physiology*
  • Mice
  • Models, Biological
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • MXI1 protein, human
  • Mxi1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Proteins