PMID- 10329706
OWN - NLM
STAT- MEDLINE
DCOM- 19990709
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 21
DP  - 1999 May 21
TI  - Hypoxia-associated induction of early growth response-1 gene expression.
PG  - 15030-40
AB  - The paradigm for the response to hypoxia is erythropoietin gene expression; 
      activation of hypoxia-inducible factor-1 (HIF-1) results in erythropoietin 
      production. Previously, we found that oxygen deprivation induced tissue factor, 
      especially in mononuclear phagocytes, by an early growth response 
      (Egr-1)-dependent pathway without involvement of HIF-1 (Yan, S.-F., Zou, Y.-S., 
      Gao, Y., Zhai, C., Mackman, N., Lee, S., Milbrandt, J., Pinsky, D., Kisiel, W., 
      and Stern, D. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 8298-8303). Now, we show 
      that cultured monocytes subjected to hypoxia (pO2 approximately 12 torr) 
      displayed increased Egr-1 expression because of de novo biosynthesis, with a 
      approximately 10-fold increased rate of transcription. Transfection of monocytes 
      with Egr-1 promoter-luciferase constructs localized elements responsible for 
      hypoxia-enhanced expression to -424/-65, a region including EBS (ets binding 
      site)-SRE (serum response element)-EBS and SRE-EBS-SRE sites. Further studies 
      with each of these regions ligated to the basal thymidine kinase promoter and 
      luciferase demonstrated that EBS sites in the element spanning -424/-375 were 
      critical for hypoxia-enhanceable gene expression. These data suggested that an 
      activated ets factor, such as Elk-1, in complex with serum response factor, was 
      the likely proximal trigger of Egr-1 transcription. Indeed, hypoxia induced 
      activation of Elk-1, and suppression of Elk-1 blocked up-regulation of Egr-1 
      transcription. The signaling cascade preceding Elk-1 activation in response to 
      oxygen deprivation was traced to activation of protein kinase C-betaII, Raf, 
      mitogen-activated protein kinase/extracellular signal-regulated protein kinase 
      kinase and mitogen-activated protein kinases. Comparable hypoxia-mediated Egr-1 
      induction and activation were observed in cultured hepatoma-derived cells 
      deficient in HIF-1beta and wild-type hepatoma cells, indicating that the HIF-1 
      and Egr-1 pathways are initiated independently in response to oxygen deprivation. 
      We propose that activation of Egr-1 in response to hypoxia induces a different 
      facet of the adaptive response than HIF-1, one component of which causes 
      expression of tissue factor, resulting in fibrin deposition.
FAU - Yan, S F
AU  - Yan SF
AD  - Department of Surgery, College of Physicians and Surgeons of Columbia University, 
      New York, New York 10032, USA.
FAU - Lu, J
AU  - Lu J
FAU - Zou, Y S
AU  - Zou YS
FAU - Soh-Won, J
AU  - Soh-Won J
FAU - Cohen, D M
AU  - Cohen DM
FAU - Buttrick, P M
AU  - Buttrick PM
FAU - Cooper, D R
AU  - Cooper DR
FAU - Steinberg, S F
AU  - Steinberg SF
FAU - Mackman, N
AU  - Mackman N
FAU - Pinsky, D J
AU  - Pinsky DJ
FAU - Stern, D M
AU  - Stern DM
LA  - eng
GR  - HL42507/HL/NHLBI NIH HHS/United States
GR  - HL55397/HL/NHLBI NIH HHS/United States
GR  - HL59488/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.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (Egr1 protein, rat)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Isoenzymes)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (Protein Kinase C beta)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.11.25 (MAP3K1 protein, human)
SB  - IM
MH  - Animals
MH  - Calcium-Calmodulin-Dependent Protein Kinases/physiology
MH  - Cell Hypoxia/*genetics
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/biosynthesis/genetics/*physiology
MH  - Early Growth Response Protein 1
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immediate-Early Proteins/biosynthesis/genetics/*physiology
MH  - Isoenzymes/physiology
MH  - *MAP Kinase Kinase Kinase 1
MH  - Nuclear Proteins/physiology
MH  - Protein Kinase C/physiology
MH  - Protein Kinase C beta
MH  - Protein Serine-Threonine Kinases/physiology
MH  - Proto-Oncogene Proteins c-raf/physiology
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Transcription Factors/biosynthesis/genetics/*physiology
EDAT- 1999/05/18 00:00
MHDA- 1999/05/18 00:01
CRDT- 1999/05/18 00:00
PHST- 1999/05/18 00:00 [pubmed]
PHST- 1999/05/18 00:01 [medline]
PHST- 1999/05/18 00:00 [entrez]
AID - S0021-9258(19)73187-1 [pii]
AID - 10.1074/jbc.274.21.15030 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 May 21;274(21):15030-40. doi: 10.1074/jbc.274.21.15030.