HIF prolyl hydroxylase 2 (PHD2) controls bone homeostasis through HIF2[alpha] - a novel player in osteohematology

2014 ◽  
Author(s):  
Martina Rauner ◽  
Kristin Franke ◽  
Lorenz C Hofbauer ◽  
Ben Wielockx
Keyword(s):  
Prolyl Hydroxylase ◽  
Bone Homeostasis ◽  
Hif Prolyl Hydroxylase

Piceatannol, a hydroxystilbene natural product, stabilizes HIF-1α protein by inhibiting HIF prolyl hydroxylase

2013 ◽  
Vol 699 (1-3) ◽  
pp. 124-131 ◽  
Author(s):  
Soohwan Yum ◽  
Hea-Jeong Doh ◽  
Sungchae Hong ◽  
Seongkeun Jeong ◽  
Dae-Duk Kim ◽  
...  
Keyword(s):  
Natural Product ◽  
Prolyl Hydroxylase ◽  
Hif Prolyl Hydroxylase

scholarly journals Lack of activity of recombinant HIF prolyl hydroxylases (PHDs) on reported non-HIF substrates

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Matthew E Cockman ◽  
Kerstin Lippl ◽  
Ya-Min Tian ◽  
Hamish B Pegg ◽  
William D Figg ◽  
...  
Keyword(s):  
Oxygen Sensors ◽  
Prolyl Hydroxylase ◽  
Hydroxylase Activity ◽  
Recombinant Enzymes ◽  
Animal Cells ◽  
Prolyl Hydroxylases ◽  
Biological Responses ◽  
Wide Range ◽  
Prolyl Hydroxylation ◽  
Hif Prolyl Hydroxylase

Human and other animal cells deploy three closely related dioxygenases (PHD 1, 2 and 3) to signal oxygen levels by catalysing oxygen regulated prolyl hydroxylation of the transcription factor HIF. The discovery of the HIF prolyl-hydroxylase (PHD) enzymes as oxygen sensors raises a key question as to the existence and nature of non-HIF substrates, potentially transducing other biological responses to hypoxia. Over 20 such substrates are reported. We therefore sought to characterise their reactivity with recombinant PHD enzymes. Unexpectedly, we did not detect prolyl-hydroxylase activity on any reported non-HIF protein or peptide, using conditions supporting robust HIF-α hydroxylation. We cannot exclude PHD-catalysed prolyl hydroxylation occurring under conditions other than those we have examined. However, our findings using recombinant enzymes provide no support for the wide range of non-HIF PHD substrates that have been reported.

scholarly journals The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2

2018 ◽  
Author(s):  
Nina Kozlova ◽  
Daniela Mennerich ◽  
Anatoly Samoylenko ◽  
Elitsa Y. Dimova ◽  
Peppi Koivunen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Survival Function ◽  
Hypoxia Inducible Factor ◽  
Adaptor Protein ◽  
Prolyl Hydroxylase ◽  
Binding Partner ◽  
And Migration ◽  
Hif Prolyl Hydroxylase ◽  
Promote Breast Cancer

SummaryThe EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.

scholarly journals Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor

2019 ◽  
Vol 48 (2) ◽  
pp. 362-378 ◽  
Author(s):  
David F. Adams ◽  
Mark S. Watkins ◽  
Luc Durette ◽  
Josée Laliberté ◽  
Félix Goulet ◽  
...  
Keyword(s):  
Cell Mass ◽  
Hypoxia Inducible Factor ◽  
Carcinogenic Risk ◽  
Prolyl Hydroxylase ◽  
High Dose ◽  
Sprague Dawley ◽  
Time Curve ◽  
Clinical Exposure ◽  
High Doses ◽  
Hif Prolyl Hydroxylase

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat’s biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat’s 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration–time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

scholarly journals A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2193-2196 ◽  
Author(s):  
Melanie J. Percy ◽  
Paul W. Furlow ◽  
Philip A. Beer ◽  
Terence R. J. Lappin ◽  
Mary Frances McMullin ◽  
...  
Keyword(s):  
Tertiary Structure ◽  
Prolyl Hydroxylase ◽  
Red Cell ◽  
Mutation Site ◽  
Α Subunit ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
Inhibitory Activities ◽  
Binding Groove ◽  
Hif Prolyl Hydroxylase

AbstractThe molecular basis of the erythrocytosis group of red cell disorders is incompletely defined. Some cases are due to dysregulation of erythropoietin (Epo) synthesis. The hypoxia inducible transcription factor (HIF) tightly regulates Epo synthesis. HIF in turn is regulated through its α subunit, which under normoxic conditions is hydroxylated on specific prolines and targeted for degradation by the von Hippel Lindau (VHL) protein. Several mutations in VHL have been reported in erythrocytosis, but only 1 mutation in the HIF prolyl hydroxylase PHD2 (prolyl hydroxylase domain protein 2) has been described. Here, we report a novel PHD2 mutation, Arg371His, which causes decreased HIF binding, HIF hydroxylase, and HIF inhibitory activities. In the tertiary structure of PHD2, Arg371 lies close to the previously described Pro317Arg mutation site. These findings substantiate PHD2 as a critical enzyme controlling HIF and therefore Epo in humans, and furthermore suggest the location of an active site groove in PHD2 that binds HIF.

scholarly journals The HIF prolyl hydroxylase PHD3 is a potential substrate of the TRiC chaperonin

FEBS Letters ◽  
2004 ◽  
Vol 570 (1-3) ◽  
pp. 166-170 ◽  
Author(s):  
Norma Masson ◽  
Rebecca J. Appelhoff ◽  
Jason R. Tuckerman ◽  
Ya-min Tian ◽  
Hans Demol ◽  
...  
Keyword(s):  
Prolyl Hydroxylase ◽  
Hif Prolyl Hydroxylase ◽  
Potential Substrate
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