Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells.

Authors:
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States
Aneesa Sataur
Aneesa Sataur
University of Pennsylvania School of Medicine
United States
Kelly L Covello
Kelly L Covello
University of Pennsylvania School of Medicine
United States
Lewis A Chodosh
Lewis A Chodosh
University of Pennsylvania School of Medicine
United States

Mol Cell Biol 2006 May;26(9):3514-26

Howard Hughes Medical Institute and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.

Transcriptional responses to hypoxia are primarily mediated by hypoxia-inducible factors (HIFs), HIF-1alpha and HIF-2alpha. The HIF-1alpha and HIF-2alpha subunits are structurally similar in their DNA binding and dimerization domains but differ in their transactivation domains, implying they may have unique target genes and require distinct transcriptional cofactors. Our previous results demonstrated that HIF-1alpha and HIF-2alpha regulate distinct target genes. Here, we report that HIF-2alpha is not transcriptionally active in embryonic stem (ES) cells, as well as possible inhibition by a HIF-2alpha-specific transcriptional repressor. Using DNA microarray analysis of hypoxia-inducible genes in wild-type (WT), Hif-1alpha(-)(/)(-), and Hif-2alpha(-)(/)(-) ES cells, we show that HIF-1alpha induces a large number of both confirmed and novel hypoxia-inducible genes, while HIF-2alpha does not activate any of its previously described targets. We further demonstrate that inhibition of HIF-2alpha function occurs at the level of transcription cofactor recruitment to endogenous target gene promoters. Overexpression of WT and, notably, a DNA-binding-defective HIF-2alpha mutant restores endogenous HIF-2alpha protein activity, suggesting that ES cells express a HIF-2alpha-specific corepressor that can be titrated by overexpressed HIF-2alpha protein. HIF-2alpha repression may explain why patients with mutations in the VHL tumor suppressor gene display cancerous lesions in specific tissue types.

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.26.9.3514-3526.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1447431PMC
May 2006
12 Reads
85 Citations
4.780 Impact Factor

Publication Analysis

Top Keywords

hif-1alpha hif-2alpha
16
hif-2alpha
11
target genes
8
stem cells
8
hif-2alpha protein
8
hypoxia-inducible genes
8
hif-1alpha
5
cells hif-1alpha
4
overexpressed hif-2alpha
4
dna microarray
4
hif-1alpha induces
4
protein hif-2alpha
4
hif-2alpha-specific corepressor
4
hif-2alpha-/- cells
4
microarray analysis
4
genes wild-type
4
wild-type hif-1alpha-/-
4
titrated overexpressed
4
repressor dna
4
corepressor titrated
4

Similar Publications