Acute postnatal ablation of Hif-2alpha results in anemia.

Authors:
Michaela Gruber
Michaela Gruber
Abramson Family Cancer Research Institute
United States
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States
Randall S Johnson
Randall S Johnson
University of California
United States
Eric J Brown
Eric J Brown
Abramson Family Cancer Research Institute
Philadelphia | United States
Brian Keith
Brian Keith
University of Pennsylvania
United States

Proc Natl Acad Sci U S A 2007 Feb 6;104(7):2301-6. Epub 2007 Feb 6.

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0608382104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892942PMC
February 2007
20 Reads
165 Citations
9.810 Impact Factor

Publication Analysis

Top Keywords

hif-2alpha
11
deletion hif-2alpha
8
acute postnatal
8
postnatal ablation
8
global deletion
8
hif-2alpha adult
4
function hif-2alpha
4
life remains
4
adult life
4
mouse development
4
demonstrating role
4
role hif-2alpha
4
hif-2alpha mouse
4
remains incompletely
4
development function
4
understood study
4
hif-2alpha allele
4
allele acute
4
ablation stringent
4
stringent conditions
4

References

(Supplied by CrossRef)
Article in Nature reviews. Molecular cell biology
Schofield et al.
Nature reviews. Molecular cell biology 2004
Article in Trends in molecular medicine
Semenza et al.
Trends in molecular medicine 2001
Article in Genes & Development
Giaccia et al.
Genes & Development 2004
Article in Science
Science 2001
Article in Science
Science 2001
Article in PNAS
Yu et al.
PNAS 2001
Article in Annual review of cell and developmental biology
Semenza et al.
Annual review of cell and developmental biology 1999
Article in Molecular and Cellular Biology
Hu et al.
Molecular and Cellular Biology 2003
Article in Genes & Development
Covello et al.
Genes & Development 2006
Article in Molecular and Cellular Biology
Seagroves et al.
Molecular and Cellular Biology 2001
Article in PNAS
Jain et al.
PNAS 1998

Similar Publications