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PMID:17284606
Citation |
Gruber, M, Hu, CJ, Johnson, RS, Brown, EJ, Keith, B and Simon, MC (2007) Acute postnatal ablation of Hif-2alpha results in anemia. Proc. Natl. Acad. Sci. U.S.A. 104:2301-6 |
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Abstract |
Adaptive transcriptional responses to oxygen deprivation (hypoxia) are mediated by the hypoxia-inducible factors (HIFs), heterodimeric transcription factors composed of two basic helix-loop-helix-PAS family proteins. The transcriptional activity of HIF is determined by the hypoxic stabilization of the HIF-alpha proteins. HIF-1alpha and HIF-2alpha exhibit high sequence homology but have different mRNA expression patterns; HIF-1alpha is expressed ubiquitously whereas HIF-2alpha expression is more restricted to certain tissues, e.g., the endothelium, lung, brain, and neural crest derivatives. Germ-line deletion of either HIF subunit is embryonic lethal with unique features suggesting important roles for both HIF-alpha isoforms. Global deletion of Hif-2alpha results in distinct phenotypes depending on the mouse strain used for the mutation, clearly demonstrating an important role for HIF-2alpha in mouse development. The function of HIF-2alpha in adult life, however, remains incompletely understood. In this study, we describe the generation of a conditional murine Hif-2alpha allele and the effect of its acute postnatal ablation. Under very stringent conditions, we ablate Hif-2alpha after birth and compare the effect of acute global deletion of Hif-2alpha and Hif-1alpha. Our results demonstrate that HIF-2alpha plays a critical role in adult erythropoiesis, with acute deletion leading to anemia. Furthermore, although HIF-1alpha was first purified and cloned based on its affinity for the human erythropoietin (EPO) 3' enhancer hypoxia response element (HRE) and regulates Epo expression during mouse embryogenesis, HIF-2alpha is the critical alpha isoform regulating Epo under physiologic and stress conditions in adults. |
Links |
PubMed PMC1892942 Online version:10.1073/pnas.0608382104 |
Keywords |
Anemia/etiology; Animals; Anoxia; Basic Helix-Loop-Helix Transcription Factors/deficiency; Basic Helix-Loop-Helix Transcription Factors/physiology; Erythropoiesis; Erythropoietin/genetics; Gene Expression Regulation; Mice; Mice, Knockout; Phenotype; Protein Isoforms/physiology; Response Elements; Stress, Physiological/genetics |
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