Neurochemical Research

, Volume 32, Issue 4–5, pp 931–946

Hypoxia Inducible Factor Prolyl 4-Hydroxylase Enzymes: Center Stage in the Battle Against Hypoxia, Metabolic Compromise and Oxidative Stress

  • Ambreena Siddiq
  • Leila R Aminova
  • Rajiv R Ratan
Original Paper

Abstract

Studies of adaptive mechanisms to hypoxia led to the discovery of the transcription factor called hypoxia inducible factor (HIF). HIF is a ubiquitously expressed, heterodimeric transcription factor that regulates a cassette of genes that can provide compensation for hypoxia, metabolic compromise, and oxidative stress including erythropoietin, vascular endothelial growth factor, or glycolytic enzymes. Diseases associated with oxygen deprivation and consequent metabolic compromise such as stroke or Alzheimer’s disease may result from inadequate engagement of adaptive signaling pathways that culminate in HIF activation. The discovery that HIF stability and activation are governed by a family of dioxygenases called HIF prolyl 4 hydroxylases (PHDs) identified a new target to augment the transcriptional activity of HIF and thus the adaptive machinery that governs neuroprotection. PHDs lose activity when cells are deprived of oxygen, iron or 2-oxoglutarate. Inhibition of PHD activity triggers the cellular homeostatic response to oxygen and glucose deprivation by stabilizing HIF and other proteins. Herein, we discuss the possible role of PHDs in regulation of both HIF-dependent and -independent cell survival pathways in the nervous system with particular attention to the co-substrate requirements for these enzymes. The emergence of neuroprotective therapies that modulate genes capable of combating metabolic compromise is an affirmation of elegant studies done by John Blass and colleagues over the past five decades implicating altered metabolism in neurodegeneration.

Keywords

Hypoxia inducible factor Prolyl 4-hydroxylase Transcriptional regulation Neuroprotection Iron chelation 

Abbreviations

AP-1

Activator protein 1

CO2

Carbon dioxide

CoCl2

Cobalt chloride

CODD

Carboxy-terminal oxygen degradation domain

DFO

Desferrioxamine

DMOG

Dimethyl-oxalyl-glycine

EGR-1

Early growth response protein-1

ERK

Extracellular signal-regulated kinase

Fe2+

Ferrous

Fe3+

Ferric

FH

Fumarate hydratase

HIF

Hypoxia inducible factor

HIF-1α

Hypoxia inducible factor-1 alpha

HIF-1β

Hypoxia inducible factor-1 beta

HRE

Hypoxia response elements

IRP2

Iron regulatory protein-2

LIP

Labile iron pool

MnSOD

Manganese Superoxide Dismutase

MORG-1

Mitogen-activated protein kinase organizer-1

NF-kB

Nuclear factor kappa B

NODD

N-terminal oxygen degradation domain

O2

Oxygen

ODD

Oxygen degradation domain

ODDD

Oxygen dependent degradation domain

PHD

prolyl 4-hydroxylase domain

PVHL

von Hippel-Lindau protein

RNA pol II

RNA polymerase II

ROS

Reactive Oxygen Species

SIAH2

Seven in absentia homolog 2

SDH

Succinate dehydrogenase

TCA

Tricarboxylic acid

VEGF

Vascular endothelial growth factor

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ambreena Siddiq
    • 1
    • 2
  • Leila R Aminova
    • 3
  • Rajiv R Ratan
    • 1
    • 2
  1. 1.Burke Medical Research InstituteNew YorkUSA
  2. 2.Departments of Neurology and NeuroscienceWeil Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of MicrobiologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA

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