PMID- 16883594
OWN - NLM
STAT- MEDLINE
DCOM- 20061026
LR  - 20181201
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 209
IP  - 2
DP  - 2006 Nov
TI  - 2-Oxoglutarate downregulates expression of vascular endothelial growth factor and 
      erythropoietin through decreasing hypoxia-inducible factor-1alpha and inhibits 
      angiogenesis.
PG  - 333-40
AB  - In oxygenated cells, hypoxia-inducible factor-1 (HIF-1) alpha subunits are 
      rapidly degraded by a mechanism that involves ubiquitination by the von 
      Hippel-Lindau tumor suppressor E3 ligase complex using 2-oxoglutarate as a 
      substrate. We examined the effect of 2-oxoglutarate on the production of 
      erythropoietin and vascular endothelial growth factor (VEGF). The expression of 
      erythropoietin and VEGF protein were dose-dependently downregulated in Hep3B 
      cells by the addition of 2-oxoglutarate. The promoter activity of VEGF-luciferase 
      was dose-dependently downregulated by the addition of 2-oxoglutarate. Gel 
      mobility shift assays revealed that the addition of 2-oxoglutarate 
      dose-dependently inhibited HIF-1 binding activity, but did not affect GATA 
      binding activity. Western blot analysis revealed that 2-oxoglutarate 
      dose-dependently inhibited the HIF-1alpha protein level in Hep3B cells in hypoxic 
      conditions. However, MG132 (the proteasome inhibitor) rescued the inhibition of 
      HIF-1alpha protein expression by 2-oxoglutarate. Furthermore, under hypoxic 
      conditions, 2-oxoglutarate dose-dependently inhibited tube formation in in vitro 
      angiogenesis assays. These results indicate that 2-oxoglutarate treatment may be 
      useful for the inhibition of angiogenesis.
CI  - Copyright 2006 Wiley-Liss, Inc.
FAU - Matsumoto, Ken
AU  - Matsumoto K
AD  - Department of Clinical and Experimental Hematology, Doctoral Program in Advanced 
      Biomedical Applications, Graduate School of Comprehensive Human Sciences, 
      University of Tsukuba, Tsukuba, Ibaraki, Japan.
FAU - Imagawa, Shigehiko
AU  - Imagawa S
FAU - Obara, Naoshi
AU  - Obara N
FAU - Suzuki, Norio
AU  - Suzuki N
FAU - Takahashi, Satoru
AU  - Takahashi S
FAU - Nagasawa, Toshiro
AU  - Nagasawa T
FAU - Yamamoto, Masayuki
AU  - Yamamoto M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (GATA Transcription Factors)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Ketoglutaric Acids)
RN  - 0 (Mutant Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 11096-26-7 (Erythropoietin)
SB  - IM
MH  - Cell Hypoxia/drug effects
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/*drug effects
MH  - Erythropoietin/*metabolism
MH  - GATA Transcription Factors/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Ketoglutaric Acids/*pharmacology
MH  - Mutant Proteins/metabolism
MH  - Neovascularization, Physiologic/*drug effects
MH  - Promoter Regions, Genetic/drug effects/genetics
MH  - Protein Binding/drug effects
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/genetics/*metabolism
EDAT- 2006/08/03 09:00
MHDA- 2006/10/27 09:00
CRDT- 2006/08/03 09:00
PHST- 2006/08/03 09:00 [pubmed]
PHST- 2006/10/27 09:00 [medline]
PHST- 2006/08/03 09:00 [entrez]
AID - 10.1002/jcp.20733 [doi]
PST - ppublish
SO  - J Cell Physiol. 2006 Nov;209(2):333-40. doi: 10.1002/jcp.20733.