PMID- 11114720
OWN - NLM
STAT- MEDLINE
DCOM- 20001228
LR  - 20181130
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 19
IP  - 48
DP  - 2000 Nov 16
TI  - Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under 
      normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor 
      suppressor gene loss of function.
PG  - 5435-43
AB  - Hypoxia induces transcription of a range of physiologically important genes 
      including erythropoietin and vascular endothelial growth factor. The 
      transcriptional activation is mediated by the hypoxia-inducible factor-1 (HIF-1), 
      a heterodimeric member of the basic helix-loop-helix PAS family, composed of 
      alpha and beta subunits. HIF-1alpha shares 48 per cent identity with the recently 
      identified HIF-2alpha protein that is also stimulated by hypoxia. In a previous 
      study of hemangioblastomas, the most frequent manifestation of hereditary von 
      Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial 
      growth factor and HIF-2alpha mRNA in stromal cells of the tumors. Mutations of 
      the VHL tumor suppressor gene are associated with a variety of tumors such as 
      renal clear cell carcinomas (RCC). In this study, we analysed the expression of 
      the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in a range of VHL 
      wildtype and VHL deficient RCC cell lines. In the presence of functional VHL 
      protein, HIF-1alpha mRNA levels are elevated, whereas HIF-2alpha mRNA expression 
      is increased only in cells lacking a functional VHL gene product. On the protein 
      levels, however, in VHL deficient cell lines, both HIF-alpha subunits are 
      constitutively expressed, whereas re-introduction of a functional VHL gene 
      restores the instability of HIF-1alpha and HIF-2alpha proteins under normoxic 
      conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas 
      demonstrate up-regulation of HIF-1alpha and HIF-2alpha in the tumor cells. The 
      data presented here provide evidence for a role of the VHL protein in regulation 
      of angiogenesis and erythropoiesis mediated by the HIF-1alpha and HIF-2alpha 
      proteins.
FAU - Krieg, M
AU  - Krieg M
AD  - Neurocenter, Freiburg University Medical School, Germany.
FAU - Haas, R
AU  - Haas R
FAU - Brauch, H
AU  - Brauch H
FAU - Acker, T
AU  - Acker T
FAU - Flamme, I
AU  - Flamme I
FAU - Plate, K H
AU  - Plate KH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Glucose Transporter Type 1)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Lymphokines)
RN  - 0 (Monosaccharide Transport Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (SLC2A1 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 6.- (Ligases)
RN  - EC 6.3.2.- (VHL protein, human)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Basic Helix-Loop-Helix Transcription Factors
MH  - Carcinoma, Renal Cell/genetics/*metabolism
MH  - Cerebellum/metabolism/physiology
MH  - DNA-Binding Proteins/*biosynthesis/genetics
MH  - Endothelial Growth Factors/biosynthesis/genetics
MH  - Genes, Tumor Suppressor/*physiology
MH  - Glucose Transporter Type 1
MH  - Hemangioblastoma/genetics/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunohistochemistry
MH  - Kidney Neoplasms/*genetics/metabolism
MH  - *Ligases
MH  - Lymphokines/biosynthesis/genetics
MH  - Monosaccharide Transport Proteins/biosynthesis/genetics
MH  - Mutation
MH  - Nuclear Proteins/*biosynthesis/genetics
MH  - Oxygen/*metabolism
MH  - Polymerase Chain Reaction
MH  - Proteins/*genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - Trans-Activators/*biosynthesis/genetics
MH  - *Transcription Factors
MH  - Tumor Cells, Cultured
MH  - *Tumor Suppressor Proteins
MH  - *Ubiquitin-Protein Ligases
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
MH  - Von Hippel-Lindau Tumor Suppressor Protein
MH  - von Hippel-Lindau Disease/genetics
EDAT- 2000/12/15 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/12/15 11:00
PHST- 2000/12/15 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/12/15 11:00 [entrez]
AID - 10.1038/sj.onc.1203938 [doi]
PST - ppublish
SO  - Oncogene. 2000 Nov 16;19(48):5435-43. doi: 10.1038/sj.onc.1203938.