Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection

Olga Aprelikova, Matthew Wood, Sean Tackett, Gadisetti V R Chandramouli, J. Carl Barrett

Research output: Contribution to journalArticle

Abstract

Tumor hypoxia often directly correlates with aggressive phenotype, metastasis progression, and resistance to chemotherapy. Two transcription factors [hypoxia-inducible factor-1α (HIF-1α) and HIF-2α] are dramatically induced in hypoxic areas and regulate the expression of genes necessary for tumor adaptation to the conditions of low oxygen; however, the relative contribution of these factors is controversial. We used RNA interference-mediated inactivation of HIF-1α or HIF-2α followed by microarray analysis to identify genes specifically regulated by either HIF-1 or HIF-2 in hypoxia. We found that, in the MCF7 cell line, the vast majority of hypoxia-responsive genes (>80%) were dependent on the presence of HIF-1α. However, a small group of genes were preferentially regulated by HIF-2α. Promoter analysis for this group of genes revealed that all of them have putative binding sites for ETS family transcription factors, and 10 of 11 HIF-2α-dependent genes had at least one potential hypoxia-responsive element (HRE) in proximity to an ETS transcription factor binding site. Knockdown of ELK-1, the most often represented member of ETS family, significantly reduced hypoxic induction of the HIF-2α-dependent genes. Physical and functional interaction between ELK-1 and HIF-2α were supported by coimmunoprecipitation of these two proteins, luciferase reporter assay using CITED2 promoter, and binding of ELK-1 protein to the promoters of CITED2 and WISP2 genes in proximity to a HRE. These data suggest that the choice of the target genes by HIF-1 or HIF-2 depends on availability and cooperation of HIFs with other factors recognizing their cognate elements in the promoters.

Original languageEnglish (US)
Pages (from-to)5641-5647
Number of pages7
JournalCancer Research
Volume66
Issue number11
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
Transcription Factors
Genes
Binding Sites
endothelial PAS domain-containing protein 1
MCF-7 Cells
Microarray Analysis
RNA Interference
Luciferases
Proteins
Oxygen
Neoplasm Metastasis
Phenotype
Gene Expression
Drug Therapy
Cell Line
Hypoxia
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. / Aprelikova, Olga; Wood, Matthew; Tackett, Sean; Chandramouli, Gadisetti V R; Barrett, J. Carl.

In: Cancer Research, Vol. 66, No. 11, 01.06.2006, p. 5641-5647.

Research output: Contribution to journalArticle

Aprelikova, Olga ; Wood, Matthew ; Tackett, Sean ; Chandramouli, Gadisetti V R ; Barrett, J. Carl. / Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. In: Cancer Research. 2006 ; Vol. 66, No. 11. pp. 5641-5647.
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