Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro.

Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Research Abstract Details 

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Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Abstract Text:

Yi Pan,Kyle D Mansfield,Cara C Bertozzi,Viktoriya Rudenko,Denise A Chan,Amato J Giaccia,M Celeste Simon,

Prolyl hydroxylation of hypoxible-inducible factor alpha (HIF-alpha) proteins is essential for their recognition by pVHL containing ubiquitin ligase complexes and subsequent degradation in oxygen (O(2))-replete cells. Therefore, HIF prolyl hydroxylase (PHD) enzymatic activity is critical for the regulation of cellular responses to O(2) deprivation (hypoxia). Using a fusion protein containing the human HIF-1alpha O(2)-dependent degradation domain (ODD), we monitored PHD activity both in vivo and in cell-free systems. This novel assay allows the simultaneous detection of both hydroxylated and nonhydroxylated PHD substrates in cells and during in vitro reactions. Importantly, the ODD fusion protein is regulated with kinetics identical to endogenous HIF-1alpha during cellular hypoxia and reoxygenation. Using in vitro assays, we demonstrated that the levels of iron (Fe), ascorbate, and various tricarboxylic acid (TCA) cycle intermediates affect PHD activity. The intracellular levels of these factors also modulate PHD function and HIF-1alpha accumulation in vivo. Furthermore, cells treated with mitochondrial inhibitors, such as rotenone and myxothiazol, provided direct evidence that PHDs remain active in hypoxic cells lacking functional mitochondria. Our results suggest that multiple mitochondrial products, including TCA cycle intermediates and reactive oxygen species, can coordinate PHD activity, HIF stabilization, and cellular responses to O(2) depletion.

Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Publishing Authors By Initials

Y Pan,KD Mansfield,CC Bertozzi,V Rudenko,DA Chan,AJ Giaccia,MC Simon,

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Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular and cellular biology

VOLUME: 27

Page Numbers: 912-25

Journal Abbreviation: Mol. Cell. Biol.

ISSN: 0270-7306

DAY: 13

MONTH: 11

YEAR: 2006

Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Information

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LANGUAGE: eng

NlmUniqueID: 8109087

Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Keywords Mesh Terms:

KEYWORDS: Von Hippel-Lindau Tumor Suppressor Prote

MESH TERMS: metabolism

Chemical & Substance for Abstract: Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Information

Substance Name: Von Hippel-Lindau Tumor Suppressor Prote

Registry Number: EC 6.3.2.19

Grant and Affiliation Information for Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro.

AFFILIATION: Howard Hughes Medical Institute, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA 104838

ACRONYM: CA

MEDLINETA: Mol Cell Biol

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