PMID- 11278891
OWN - NLM
STAT- MEDLINE
DCOM- 20010531
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 16
DP  - 2001 Apr 20
TI  - Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of 
      hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP.
PG  - 12645-53
AB  - Endothelin-1 (ET-1) is a peptide hormone with potent vasoconstrictor properties 
      which is synthesized and secreted predominantly by vascular endothelial cells. 
      Its production is regulated by numerous stimuli including ischemia and hypoxia, 
      and the enhanced levels that occur during myocardial ischemia may contribute to 
      the progression of heart failure. We reported previously a preliminary 
      characterization of a hypoxia-inducible factor-1 (HIF-1) binding site in the 
      human ET-1 promoter which contributed to the activation of ET-1 expression in 
      endothelial cells. We report here that the HIF-1 binding site alone is not 
      sufficient for the response to hypoxia but requires an additional 50 base pairs 
      of flanking sequence that includes binding sites for the factors activator 
      protein-1 (AP-1), GATA-2, and CAAT-binding factor (NF-1). Mutation of any one of 
      these sites or the HIF-1 site eliminated induction by hypoxia. Mutations of the 
      AP-1 and GATA-2 sites, but not the HIF-1 site, were complemented by 
      overexpressing AP-1, GATA-2, HIF-1alpha, or the activator protein p300/CBP, 
      restoring the response to hypoxia. Binding studies in vitro confirmed physical 
      associations among GATA-2, AP-1, and HIF-1 factors. Overexpression or depletion 
      of p300/CBP modulated the level of ET-1 promoter expression as well as the 
      endogenous ET-1 transcript but did not change the fold induction by hypoxia in 
      either case. Regulation of the ET-1 promoter by hypoxia in non-endothelial cells 
      required overexpression of GATA-2 and HIF-1alpha. The results support essential 
      roles for AP-1, GATA-2, and NF-1 in stabilizing the binding of HIF-1 and 
      promoting recruitment of p300/CBP to the ET-1 hypoxia response complex.
FAU - Yamashita, K
AU  - Yamashita K
AD  - Department of Molecular and Cellular Pharmacology, University of Miami Medical 
      Center, Miami, Florida 33149, USA.
FAU - Discher, D J
AU  - Discher DJ
FAU - Hu, J
AU  - Hu J
FAU - Bishopric, N H
AU  - Bishopric NH
FAU - Webster, K A
AU  - Webster KA
LA  - eng
GR  - HL44578/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20010122
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Endothelin-1)
RN  - 0 (GATA2 Transcription Factor)
RN  - 0 (GATA2 protein, human)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Base Sequence
MH  - Binding Sites
MH  - Cell Hypoxia/*physiology
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/*metabolism
MH  - Endothelin-1/*genetics
MH  - Endothelium, Vascular/cytology/*metabolism
MH  - GATA2 Transcription Factor
MH  - Gene Expression Regulation/*physiology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Kinetics
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Nuclear Proteins/*metabolism
MH  - *Promoter Regions, Genetic
MH  - Recombinant Proteins/metabolism
MH  - Sequence Deletion
MH  - Trans-Activators/*metabolism
MH  - Transcription Factor AP-1/*metabolism
MH  - Transcription Factors/*metabolism
MH  - Umbilical Veins
MH  - Zinc Fingers
EDAT- 2001/03/30 10:00
MHDA- 2001/06/02 10:01
CRDT- 2001/03/30 10:00
PHST- 2001/03/30 10:00 [pubmed]
PHST- 2001/06/02 10:01 [medline]
PHST- 2001/03/30 10:00 [entrez]
AID - S0021-9258(19)34364-9 [pii]
AID - 10.1074/jbc.M011344200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Apr 20;276(16):12645-53. doi: 10.1074/jbc.M011344200. Epub 2001 
      Jan 22.