Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors

Olga Aprelikova, Gadisetti V.R. Chandramouli, Matthew Wood, James R. Vasselli, Joseph Riss, Jodi K. Maranchie, W. Marston Linehan, J. Carl Barrett

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Hypoxia and induction of hypoxia-inducible factors (HIF-1α and HIF-2α) is a hallmark of many tumors. Under normal oxygen tension HIF-alpha subunits are rapidly degraded through prolyl hydroxylase dependent interaction with the von Hippel-Lindau (VHL) tumor suppressor protein, a component of E3 ubuiquitin ligase complex. Using microarray analysis of VHL mutated and re-introduced cells, we found that one of the prolyl hydroxylases (PHD3) is coordinately expressed with known HIF target genes, while the other two family members (PHD1 and 2) did not respond to VHL. We further tested the regulation of these genes by HIF-1 and HIF-2 and found that siRNA targeted degradation of HIF-1α and HIF-2α results in decreased hypoxia-induced PHD3 expression. Ectopic overexpression of HIF-2α in two different cell lines provided a much better induction of PHD3 gene than HIF-1α. In contrast, we demonstrate that PHD2 is not affected by overexpression or downregulation of HIF-2α. However, induction of PHD2 by hypoxia has HIF-1-independent and -dependent components. Short-term hypoxia (4 h) results in induction of PHD2 independent of HIF-1, while PHD2 accumulation by prolonged hypoxia (16 h) was decreased by siRNA-mediated degradation of HIF-1α subunit. These data further advance our understanding of the differential role of HIF factors and putative feedback loop in HIF regulation.

Original languageEnglish (US)
Pages (from-to)491-501
Number of pages11
JournalJournal of cellular biochemistry
Volume92
Issue number3
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Fingerprint

Prolyl Hydroxylases
Genes
Small Interfering RNA
Von Hippel-Lindau Tumor Suppressor Protein
Degradation
Ubiquitin-Protein Ligases
Microarrays
Tumors
Hypoxia-Inducible Factor 1
Cells
Oxygen
Feedback
Microarray Analysis
Down-Regulation
Hypoxia
Cell Line
Neoplasms

Keywords

  • HIF
  • Hypoxia
  • Microarray
  • Prolyl hydroxylases
  • siRNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Aprelikova, O., Chandramouli, G. V. R., Wood, M., Vasselli, J. R., Riss, J., Maranchie, J. K., ... Barrett, J. C. (2004). Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. Journal of cellular biochemistry, 92(3), 491-501. https://doi.org/10.1002/jcb.20067

Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. / Aprelikova, Olga; Chandramouli, Gadisetti V.R.; Wood, Matthew; Vasselli, James R.; Riss, Joseph; Maranchie, Jodi K.; Linehan, W. Marston; Barrett, J. Carl.

In: Journal of cellular biochemistry, Vol. 92, No. 3, 01.12.2004, p. 491-501.

Research output: Contribution to journalArticle

Aprelikova, O, Chandramouli, GVR, Wood, M, Vasselli, JR, Riss, J, Maranchie, JK, Linehan, WM & Barrett, JC 2004, 'Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors', Journal of cellular biochemistry, vol. 92, no. 3, pp. 491-501. https://doi.org/10.1002/jcb.20067
Aprelikova O, Chandramouli GVR, Wood M, Vasselli JR, Riss J, Maranchie JK et al. Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. Journal of cellular biochemistry. 2004 Dec 1;92(3):491-501. https://doi.org/10.1002/jcb.20067
Aprelikova, Olga ; Chandramouli, Gadisetti V.R. ; Wood, Matthew ; Vasselli, James R. ; Riss, Joseph ; Maranchie, Jodi K. ; Linehan, W. Marston ; Barrett, J. Carl. / Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. In: Journal of cellular biochemistry. 2004 ; Vol. 92, No. 3. pp. 491-501.
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