HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress

Singh, Rashim; Franke, Kristin; Kalucka, Joanna; Mamlouk, Soulafa; Muschter, Antje; Gembarska, Agnieszka; Grinenko, Tatyana; Willam, Carsten; Naumann, Ronald; Anastassiadis, Konstantinos; Stewart, Aengus; Bornstein, Stefan R.; Chavakis, Triantafyllos; Breier, Georg; Waskow, Claudia; Wielockx, Ben

doi:10.1182/blood-2012-12-471185

Cited by 44 publications

(41 citation statements)

References 37 publications

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“…Although we did not observe differences in white blood cell or platelet counts in the Vav1-Cre; Phd2 f/f mice, it is conceivable that hematopoietic stem cell/progenitor cells may be altered upon Phd2 loss. Evidence for this has recently been presented (54).…”

Section: Discussionmentioning

confidence: 88%

A Knock-in Mouse Model of Human PHD2 Gene-associated Erythrocytosis Establishes a Haploinsufficiency Mechanism

Arsenault

Pei

Lee

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 88%

A Knock-in Mouse Model of Human PHD2 Gene-associated Erythrocytosis Establishes a Haploinsufficiency Mechanism

Arsenault

Pei

Lee

et al. 2013

Journal of Biological Chemistry

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“…Knockout mice for this isoform die of placental and cardiac defects between embryonic days 12.5 and 14.5 as a result of an underdeveloped myocardium and trabeculae, as well as poor vascular branching in the placenta 36,37. Therefore, only the use of conditional deletion approaches has been possible to study the role of this enzyme in vivo.…”

Section: Hif Prolyl-4-hydroxylase Domain Enzymesmentioning

confidence: 99%

“…Mice lacking PHD2 in CD68-expressing cells (eg, all hematopoietic cells, different epithelial cell lineages, and EPO producing cells)37 exhibited an excessive EPO production in both kidney and brain, with severely increased hematocrit (up to 85%), thrombocytopenia, and splenomegaly. Further deletion of HIF2α in these mice abolished the erythrocytosis phenotype, whereas deletion of HIF1α had no effect on the outcome.…”

Section: The Role Of Phd2 In Pathologymentioning

confidence: 99%

PHD2: from hypoxia regulation to disease progression

Meneses¹,

Wielockx²

2016

Self Cite

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Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential.

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“…The common shared targets are VEGF, GLUT-1, GLUT-3, and HK2. HIF-1α exclusively stimulates the expression of several glycolytic enzymes, whereas the embryonic transcription factors Oct-4, cyclin D1, platelet-derived growth factor (PDGF), and erythropoietin (EPO) are activated in a HIF-2α-dependent manner (Figure 2) (Florczyk, et al 2011; Franke, et al 2013; Furlow, et al 2009; Koh, et al 2011; Patel and Simon 2008; Rankin, et al 2007; Singh, et al 2013). The differential effects of these two transcription factors in numerous cellular systems are now well established and reviewed, including their link to the pathogenesis of PHEO and PGL (Branco-Price, et al 2012; Chiavarina, et al 2012; Holmquist-Mengelbier, et al 2006; Jochmanova, et al 2013; Keith et al 2012; Koh et al 2011; Semenza 2012).…”

Section: Sdh Dysfunction and Metabolic Changesmentioning

confidence: 99%

Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma

Vícha¹,

Taïeb²,

Pacák³

2014

Endocrine-Related Cancer

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Warburg’s metabolic hypothesis is based on the assumption that a cancer cell’s respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma/paraganglioma. Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species (ROS), and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor (HIF)) including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic pheochromocytomas/paragangliomas, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.

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HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress

Abstract: Key Points Loss of the oxygen sensor PHD2 in the HSC compartment in mice results in the HIF1α-driven induction of multipotent progenitors. PHD2-deficient hematopoietic progenitors are outcompeted during severe stress while HSCs are encouraged to self-renew.

Cited by 44 publications

References 37 publications

A Knock-in Mouse Model of Human PHD2 Gene-associated Erythrocytosis Establishes a Haploinsufficiency Mechanism

A Knock-in Mouse Model of Human PHD2 Gene-associated Erythrocytosis Establishes a Haploinsufficiency Mechanism

PHD2: from hypoxia regulation to disease progression

Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma

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