The HIF family member EPAS1/HIF-2α is required for normal hematopoiesis in mice

Scortegagna, Marzia; Morris, Margaret A.; Oktay, Yavuz; Bennett, Michael J.; Garcia, Joseph A.

doi:10.1182/blood-2003-02-0448

Cited by 180 publications

(169 citation statements)

References 49 publications

(49 reference statements)

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“…Strikingly, the midgestational death was rescued by feeding the mothers DOPS, a substance that can directly convert into norepinephrine. Although a sympathetic phenotype was less pronounced in other Hif2a -/-mice -particularly as a cause of death -altered catecholamine content or DOPSmediated rescue was recorded at least to some degree in all other Hif2a knockout animals (Peng et al 2000;Compernolle et al 2002;Scortegagna et al 2003). These findings are consistent with the reported role of Hif2a in activating transcription of the DDC and DBH enzymes and thereby regulating catecholamine synthesis in fetal rat sympathoadrenal progenitor cells regardless of oxygen tension ).…”

Section: Hif-2 During Normal Sympathetic Nervous System (Sns) Developsupporting

confidence: 85%

“…Despite displaying incompletely overlapping phenotypes, four different Hif2a knockout mice have been instrumental in identifying putative roles for HIF2A during normal development (Tian et al 1998;Peng et al 2000;Compernolle et al 2002;Scortegagna et al 2003). While Hif1a -/-animals are dead by embryonic day E11 with severe disorganization of vascular networks and gross neural tube defects, the effects of eliminating Hif2a -at least during early development -appears less general.…”

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

“…Creating Hif2a -/-animals by hybrid mating allowed Scortegagna et al (Scortegagna et al 2003) to study effects of Hif2a loss in the post-natal mouse. These mice suffered from biochemical/metabolic abnormalities and multiple-organ pathology, specifically in sites of high-energy demand including the heart, liver, testis and bone marrow, indicating a syndrome related or similar to mitochondrial disease.…”

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

“…In addition, Hif2a -/-mice display defects in hematopoietic development due to greatly reduced EPO levels in the kidney (Scortegagna et al 2003;Scortegagna et al 2005;Rankin et al 2007). Administration of exogenous EPO reverts this phenotype as well as some of the other defects associated with Hif2a elimination (Scortegagna et al 2005).…”

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

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The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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Section: Hif-2 During Normal Sympathetic Nervous System (Sns) Developsupporting

confidence: 85%

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 99%

See 2 more Smart Citations

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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“…We suggested that this was mainly due to partial inhibition of HIF-1a expression by shRNAs tested here, but the possibility could not be excluded that some other hypoxia-responsive elements also contribute to hypoxia-induced differentiation. If this is true, HIF-2a (the second member of the HIF family) should be considered as one of the candidates, because it was reported to be required for normal hematopoiesis in mice (Scortegagna et al, 2003). HIF-1a/HIF-1b heterodimer acts as a transcription factor through binding to the hypoxia-responsive element in the cis-acting sequences (Semenza, 2000).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

Wang

Zhang

et al. 2007

Oncogene

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Hypoxia or hypoxia mimetic has been shown to induce differentiation together with the accumulation of hypoxiainducible factor-1a (HIF-1a) protein of myeloid leukemic cells and normal hematopoietic progenitors. To provide direct evidence for the role of HIF-1a in acute myeloid leukemia (AML) cell differentiation and its mechanisms, we generated myeloid leukemic U937T transformants, in which HIF-1a was tightly induced by tetracycline withdrawal. The results showed that the conditional HIF-1a induction triggered granulocytic differentiation of these transformants, while the suppression of HIF-1a expression by specific short hairpin RNAs (shRNAs) effectively inhibited hypoxia-induced differentiation of U937 cells, as evidenced by morphology, maturation-related antigens as well as expressions of myeloid differentiation signatures and hematopoietic cells-specific cytokine receptors. The specific shRNAs-inhibited expression of HIF-1b, an essential partner for transcription activity of HIF-1, failed, while the inhibition of hematopoietic differentiation-critical CCAAT/enhancer-binding protein-a (C/EBPa) significantly eliminated HIF-1a-mediated myeloid leukemic cell differentiation. Collectively, this work provided several lines of direct evidence for the role of HIF-1a protein through its nontranscriptional activity in myeloid cell differentiation, in which C/EBPa elicits a role as an effector downstream to HIF-1a. These discoveries would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of AML.

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Hypoxic Response and Associated Diseases

Emily¹,

Loenarz²,

Schofield³

2008

Wiley Encyclopedia of Chemical Biology

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Animals must respond efficiently to changes in oxygen levels. This response is achieved via oxygen‐dependent regulation of a heterodimeric hypoxia‐inducible transcription factor (HIF), which enables upregulation of genes that assist in the hypoxic response. Posttranslational hydroxylation of the HIF‐α subunit at either of two conserved prolyl residues enables binding to the von Hippel–Lindau protein elongin C/B complex that targets HIF‐α for degradation via the ubiquitin proteasome pathway. Hydroxylation of an asparaginyl residue in the C‐terminal transcriptional activation domain of HIF‐α blocks its interaction with the transcriptional coactivator p300. The HIF prolyl and asparaginyl hydroxylases are oxygen dependent; therefore, their regulation of HIF directly links changes in oxygen concentration and the physiological response to hypoxia. The hypoxic response is implicated in a range of disease states, including cancer, ischemia, and heart disease. Manipulation of the HIF system for therapeutic advantage is therefore an area of medicinal interest.

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The HIF family member EPAS1/HIF-2α is required for normal hematopoiesis in mice

Cited by 180 publications

References 49 publications

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

Hypoxic Response and Associated Diseases

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