Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor*

By R. Appelhoff, Ya-min Tian, R. Raval, H. Turley, Adrian L. Harris, C. Pugh, P. Ratcliffe, J. Gleadle. Journal of Biological Chemistry, 2004

1,117 citations recorded by the source corpus.

Hypoxia-inducible factor (HIF) is a transcriptional regulator that plays a key role in many aspects of oxygen homeostasis. The heterodimeric HIF complex is regulated by proteolysis of its α-subunits, following oxygen-dependent hydroxylation of specific prolyl residues. Although three HIF prolyl hydroxylases, PHD1, PHD2, and PHD3, have been identified that have the potential to catalyze this reaction, the contribution of each isoform to the physiological regulation of HIF remains uncertain. Here we show using suppression by small interference RNA that each of the three PHD isoforms contributes in a non-redundant manner to the regulation of both HIF-1α and HIF-2α subunits and that the contribution of each PHD under particular culture conditions is strongly dependent on the abundance of the enzyme. Thus in different cell types, isoform-specific patterns of PHD induction by hypoxia and estrogen alter both the relative abundance of the PHDs and their relative contribution to the regulation of HIF. In addition, the PHDs manifest specificity for different prolyl hydroxylation sites within each HIF-α subunit, and a degree of selectively between HIF-1α and HIF-2α isoforms, indicating that differential PHD inhibition has the potential to selectively alter the characteristics of HIF activation.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c5c121c8c46c3b53267f3c7756d9e519cf3c44ec

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In Cancer Research

1. G. Semenza
2. P. Schumacker
3. M. C. Simon
4. Craig B. Thompson
5. R. Guzy
6. W. Kaelin
7. Eyal Gottlieb
8. P. Ratcliffe

In Genetics

1. V. Haase
2. P. Schumacker
3. R. Guzy
4. J. Richards
5. M. C. Simon
6. W. Kaelin
7. J. Espinosa
8. Craig B. Thompson

In Molecular Biology

1. P. Schumacker
2. M. C. Simon
3. W. Kaelin
4. R. Guzy
5. P. Ratcliffe
6. G. Semenza
7. Craig B. Thompson
8. Eyal Gottlieb

Citations in the corpus

• Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. (2005, background): “Recent experiments using suppression by small interference RNA showed that each contributes in a nonredundant manner to the regulation of both HIF-1 and HIF-2 subunits and that the contribution of each PHD is strongly dependent on the abundance of the enzyme (71).”
• Hypoxia-Inducible Factor-1 (HIF-1) (2006, neutral): “In addition, several second messengers have also been shown to modify the activity of PHDs (Appelhoff et al., 2004; Hirota et al., 2004; Temes et al., 2005).”
• Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and its Potential for Therapeutic Intervention in Malignancy and Ischemia (2007, background): “Much remains to learn about the selectivity and properties of factors influencing the HIF-1 pathway [51].”
• Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “In normoxia, a family of prolyl-4-hydroxylases (PHD1-4), most prominently PHD2 (also known as EGLN1), hydroxylate the oxygen-sensitive alpha subunits (Appelhoff, 2004; Berra et al., 2003; Koivunen et al., 2007; Landazuri et al., 2006).”
• Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia (2006, background): “Prolyl hydroxylases (PH) are a family of mixed function oxidases involved in the post-translational modification that signals HIF-α for degradation (Tanimoto et al. 2000; Clifton et al. 2001; Epstein et al. 2001; Bruick & McKnight, 2001; Berra et al. 2003; Appelhoff et al. 2004).”
• Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. (2008, background): “It is also relatively more effective in suppression of HIF2a and so might alter the relative abundance of HIF2a versus HIF1a (Appelhoff et al., 2004).”
• Regulation of erythropoiesis by hypoxia-inducible factors (2013, background): “Furthermore, PHD1 and PHD3 appear to preferentially target HIF-2α in vitro and in vivo, which offers potential for therapeutic exploitation under conditions in which HIF-1 activation is non-desirable.(239,242) Aside from stimulating endogenous EPO synthesis, pharmacological”
• The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017, positive): “An important determinant of HIF-1α activity relative to HIF-2α activity is the abundance of specific PHD enzymes, which have differential specificities for prolyl hydroxylation sites between the HIFα isoforms (5).”
• Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. (2005, methodology): “In vitro translated HA-tagged ODD domain was ity of HIF-1 and HIF-2 , respectively (Appelhoff et al., 2004), used as a substrate, and cell extracts were used as a source of and these enzymes may exhibit differences in their response to PHD activity.”
• Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. (2005, background): “This dilemma may be explained if the contribution of each isoform to HIF hydroxylation depends on its relative abundance in a given cell type and a given culture condition, and if all three function in a nonredundant fashion (Appelhoff et al., 2004).”
• Chapter 10 Metabolic and Molecular Responses of Fish to Hypoxia (2009, methodology): “Biochemical analysis has shown PHD 2 to have a higher aYnity for HIF 1a, whereas PHD 1 and PDH 3 have higher aYnity for HIF 2a (AppelhoV et al., 2004).”