The Length of Peptide Substrates Has a Marked Effect on Hydroxylation by the Hypoxia-inducible Factor Prolyl 4-Hydroxylases

Koivunen, Peppi; Hirsilä, Maija; Kivirikko, Kari I.; Myllyharju, Johanna

doi:10.1074/jbc.m604628200

Cited by 114 publications

(110 citation statements)

References 34 publications

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“…Regulation of all four HIF hydroxylases by the citric acid cycle intermediates fumarate, succinate and oxaloacetate was investigated, with the PHDs exhibiting negative regulation with all three. 49,50 FIH-1, however, was not inhibited by physiologically relevant levels of these compounds, and is thus unlikely to be regulated via metabolic pathway intermediates, possibly due to its more important role in other processes not directly related to cellular metabolism, including neural differentiation and vasculogenesis. Understanding of the regulation of FIH-1 expression and the consequences for HIF activity is limited and warrants further investigation.…”

Section: Regulation Of Fih-1mentioning

confidence: 96%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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Section: Regulation Of Fih-1mentioning

confidence: 96%

Turn me on: regulating HIF transcriptional activity

2008

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“…The most extensively studied prolyl hydroxylases are the ones that hydroxylate a proline residues in collagen molecules (8)(9)(10)(11)(12)(13). These studies reveal that the enzyme, isolated as a homogeneous protein by affinity chromatography from three different sources (8)(9)(10)12,14,15), occurs as a tetramer with a molecular weight of about 240,000 (11,(16)(17)(18). The enzyme does not hydroxylate free proline, and recognizes a conserved motif (LXXLAP in the HIF-1 molecule; X indicates any amino acid and P indicates the hydroxyl acceptor proline) in the primary substrate for hydroxylation (5,11,(19)(20)(21)(22).…”

Section: Regulation Of Prolyl 4-hydroxylase (Phd) Enzyme Activity Viamentioning

confidence: 99%

Prolyl 4-hydroxylase activity-responsive transcription factors: From hydroxylation to gene expression and neuroprotection

Siddiq

Aminova²,

Ratan³

2008

Front Biosci

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Most homeostatic processes including gene transcription occur as a result of deviations in physiological tone that threatens the survival of the organism. A prototypical homeostatic stress response includes changes in gene expression following alterations in oxygen, iron or 2-oxoglutarate levels. Each of these cofactors plays an important role in cellular metabolism. Accordingly, a family of enzymes known as the Prolyl 4-hydroxylase (PHD) enzymes are a group of dioxygenases that have evolved to sense changes in 2-oxoglutarate, oxygen and iron via changes in enzyme activity. Indeed, PHDs are a part of an established oxygen sensor system that regulates transcriptional regulation of hypoxia/stress-regulated genes and thus are an important component of events leading to cellular rescue from oxygen, iron or 2-oxoglutarate deprivations. The ability of PHD activity to regulate homeostatic responses to oxygen, iron or 2-oxoglutarate metabolism has led to the development of small molecule inhibitors of the PHDs as a strategy for activating or augmenting cellular stress responses. These small molecules are proving effective in preclinical models of stroke and Parkinson's disease. However the precise protective pathways engaged by PHD inhibition are only beginning to be defined. In the current review, we summarize the role of iron, 2-oxoglutarate and oxygen in the PHD catalyzed hydroxylation reaction and provide a brief discussion of some of the transcription factors that play an effective role in neuroprotection against oxidative stress as a result of changes in PHD activity.

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“…Indeed, biochemical in vitro studies revealed K m values of purified PHDs for oxygen close to the oxygen partial pressure (pO 2 ) in air, suggesting that the kinetics of specific HIFα hydroxylation under hypoxic conditions are rather slow (Ehrismann et al, 2006;Hirsilä et al, 2003). Of note, these K m values are critically dependent on the length of the target peptide (Koivunen et al, 2006). However, tissues in situ have to deal with a great variability of generally very low pO 2 values, even when the inspiratory pO 2 is considered to be "normoxic".…”

Section: Introductionmentioning

confidence: 99%