PMID- 9159130
OWN - NLM
STAT- MEDLINE
DCOM- 19970619
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 94
IP  - 11
DP  - 1997 May 27
TI  - Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and 
      conformational change by recruitment of the Arnt transcription factor.
PG  - 5667-72
AB  - In response to hypoxia the hypoxia-inducible factor-1 (HIF-1) mediates 
      transcriptional activation of a network of genes encoding erythropoietin, 
      vascular endothelial growth factor, and several glycolytic enzymes. HIF-1 
      consists of a heterodimer of two basic helix-loop-helix PAS (Per/Arnt/Sim) 
      proteins, HIF-1alpha and Arnt. HIF-1alpha and Arnt mRNAs are constitutively 
      expressed and were not altered upon exposure of HeLa or HepG2 cells to hypoxia, 
      suggesting that the activity of the HIF-1alpha-Arnt complex may be regulated by 
      some as yet unknown posttranscriptional mechanism. In support of this model, we 
      demonstrate here that Arnt protein levels were not increased under conditions 
      that induce an hypoxic response in HeLa and HepG2 cells. However, under identical 
      conditions, HIF-1alpha protein levels were rapidly and dramatically up-regulated, 
      as assessed by immunoblot analysis. In addition, HIF-1alpha acquired a new 
      conformational state upon dimerization with Arnt, rendering HIF-1alpha more 
      resistant to proteolytic digestion in vitro. Dimerization as such was not 
      sufficient to elicit the conformational change in HIF-1alpha, since truncated 
      forms of Arnt that are capable of dimerizing with HIF-1alpha did not induce this 
      effect. Moreover, the high affinity DNA binding form of the HIF-1alpha-Arnt 
      complex was only generated by forms of Arnt capable of eliciting the allosteric 
      change in conformation. In conclusion, the combination of enhanced protein levels 
      and allosteric change by dimerization defines a novel mechanism for modulation of 
      transcription factor activity.
FAU - Kallio, P J
AU  - Kallio PJ
AD  - Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska 
      Institutet, S-171 77 Stockholm, Sweden.
FAU - Pongratz, I
AU  - Pongratz I
FAU - Gradin, K
AU  - Gradin K
FAU - McGuire, J
AU  - McGuire J
FAU - Poellinger, L
AU  - Poellinger L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (ARNT protein, human)
RN  - 0 (Arnt protein, mouse)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Transcription Factors)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
SB  - IM
MH  - Animals
MH  - Aryl Hydrocarbon Receptor Nuclear Translocator
MH  - Carcinoma, Hepatocellular
MH  - Cell Hypoxia
MH  - Cloning, Molecular
MH  - DNA-Binding Proteins/biosynthesis/chemistry/*metabolism
MH  - Dimerization
MH  - HeLa Cells
MH  - Helix-Loop-Helix Motifs
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Liver Neoplasms
MH  - Mice
MH  - Models, Structural
MH  - Mutagenesis
MH  - Nuclear Proteins/biosynthesis/chemistry/*metabolism
MH  - Protein Binding
MH  - Protein Biosynthesis
MH  - *Protein Conformation
MH  - Protein Multimerization
MH  - RNA, Messenger/biosynthesis
MH  - *Receptors, Aryl Hydrocarbon
MH  - Recombinant Fusion Proteins/biosynthesis/metabolism
MH  - Reticulocytes/metabolism
MH  - Sequence Deletion
MH  - Transcription Factors/biosynthesis/chemistry/*metabolism
MH  - Transcription, Genetic
MH  - Triticum/metabolism
MH  - Tumor Cells, Cultured
PMC - PMC20836
EDAT- 1997/05/27 00:00
MHDA- 1997/05/27 00:01
PMCR- 1997/11/27
CRDT- 1997/05/27 00:00
PHST- 1997/05/27 00:00 [pubmed]
PHST- 1997/05/27 00:01 [medline]
PHST- 1997/05/27 00:00 [entrez]
PHST- 1997/11/27 00:00 [pmc-release]
AID - 0976 [pii]
AID - 10.1073/pnas.94.11.5667 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1997 May 27;94(11):5667-72. doi: 
      10.1073/pnas.94.11.5667.