PMID- 16849552
OWN - NLM
STAT- MEDLINE
DCOM- 20060919
LR  - 20181113
IS  - 0008-5472 (Print)
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 14
DP  - 2006 Jul 15
TI  - Early growth response gene-1 regulates hypoxia-induced expression of tissue 
      factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent 
      mechanisms.
PG  - 7067-74
AB  - Hypoxia strongly up-regulates tissue factor and promotes plasma clotting by 
      glioblastoma multiforme, but transcriptional mechanisms remain undefined. Here, 
      we investigated the potential roles of early growth response gene-1 (Egr-1), Sp1, 
      nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and 
      hypoxia-inducible factor-1 (HIF-1) in the hypoxic regulation of tissue factor by 
      glioblastoma multiforme cells in vitro. Hypoxia (1% O2) strongly induced Egr-1 
      mRNA within 1 hour and led to nuclear localization of Egr-1 protein. Using 
      luciferase reporter plasmids in glioma cells, we found that hypoxia dramatically 
      increased luciferase activity in cells with constructs containing Egr-1-binding 
      sites but not in cells with constructs containing AP-1- or NF-kappaB-binding 
      sites. Electrophoretic mobility shift assays revealed hypoxia-induced Egr-1, but 
      not Sp1, binding to oligonucleotides containing the Egr-1/Sp1 motif of tissue 
      factor gene promoter. Using an expression vector containing the minimal tissue 
      factor promoter (-111 to +14 bp) and small interfering RNA (siRNA) directed at 
      Egr-1 and Sp1 mRNAs, we found that Egr-1 was required for maximal hypoxic 
      induction of promoter activity. Forced overexpression of Egr-1 but not Sp1 by 
      cDNA transfection caused up-regulation of tissue factor in glioma cells under 
      normoxia (21% O2), whereas siRNA directed at Egr-1 strongly attenuated 
      hypoxia-induced tissue factor expression. To examine the effects of HIF-1alpha on 
      tissue factor expression, we used glioma cells stably transfected with a 
      HIF-1alpha siRNA expression vector and found that HIF-1alpha mRNA silencing did 
      not affect tissue factor expression under hypoxia. We conclude that hypoxic 
      up-regulation of tissue factor in glioblastoma multiforme cells depends largely 
      on Egr-1 and is independent of HIF-1.
FAU - Rong, Yuan
AU  - Rong Y
AD  - Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, Georgia 30322, USA.
FAU - Hu, Fang
AU  - Hu F
FAU - Huang, Ruopan
AU  - Huang R
FAU - Mackman, Nigel
AU  - Mackman N
FAU - Horowitz, Jonathan M
AU  - Horowitz JM
FAU - Jensen, Randy L
AU  - Jensen RL
FAU - Durden, Donald L
AU  - Durden DL
FAU - Van Meir, Erwin G
AU  - Van Meir EG
FAU - Brat, Daniel J
AU  - Brat DJ
LA  - eng
GR  - R01 CA086335/CA/NCI NIH HHS/United States
GR  - CA-109382/CA/NCI NIH HHS/United States
GR  - R01 CA087830/CA/NCI NIH HHS/United States
GR  - R21 CA109382/CA/NCI NIH HHS/United States
GR  - R01 NS053727/NS/NINDS NIH HHS/United States
GR  - CA-86335/CA/NCI NIH HHS/United States
GR  - R01 NS053727-03/NS/NINDS NIH HHS/United States
GR  - NS-42934/NS/NINDS NIH HHS/United States
GR  - CA-87830/CA/NCI NIH HHS/United States
GR  - K08 NS042934/NS/NINDS NIH HHS/United States
GR  - NS053727/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (EGR1 protein, human)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (NF-kappa B)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (Sp1 Transcription Factor)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9035-58-9 (Thromboplastin)
SB  - IM
MH  - Cell Hypoxia/physiology
MH  - Cell Line, Tumor
MH  - Early Growth Response Protein 1/biosynthesis/*genetics
MH  - Glioblastoma/*genetics/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/biosynthesis/*genetics
MH  - NF-kappa B/biosynthesis/genetics
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins c-jun/biosynthesis/genetics
MH  - Sp1 Transcription Factor/biosynthesis/genetics
MH  - Thromboplastin/*biosynthesis/genetics
MH  - Transcription Factor AP-1/biosynthesis/genetics
MH  - Transfection
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/genetics
PMC - PMC2610484
MID - NIHMS82093
EDAT- 2006/07/20 09:00
MHDA- 2006/09/20 09:00
PMCR- 2008/12/29
CRDT- 2006/07/20 09:00
PHST- 2006/07/20 09:00 [pubmed]
PHST- 2006/09/20 09:00 [medline]
PHST- 2006/07/20 09:00 [entrez]
PHST- 2008/12/29 00:00 [pmc-release]
AID - 66/14/7067 [pii]
AID - 10.1158/0008-5472.CAN-06-0346 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Jul 15;66(14):7067-74. doi: 10.1158/0008-5472.CAN-06-0346.