HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells

Exp Cell Res. 2009 Jul 1;315(11):1924-36. doi: 10.1016/j.yexcr.2009.02.015. Epub 2009 Feb 27.

Abstract

Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Hypoxia / genetics
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Genes, myc
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • Transfection
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics*
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MXI1 protein, human
  • RNA, Small Interfering
  • Tumor Suppressor Proteins