PMID- 11514583
OWN - NLM
STAT- MEDLINE
DCOM- 20011207
LR  - 20220408
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 43
DP  - 2001 Oct 26
TI  - Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators 
      nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and 
      phenylarsine oxide.
PG  - 39805-11
AB  - Hypoxic/ischemic conditions provoke activation of the hypoxia-inducible factor-1 
      (HIF-1), which functions as a transcription factor. HIF-1 is composed of the 
      HIF-1alpha and -beta subunits, and stability regulation occurs via 
      accumulation/degradation of HIF-1alpha with the notion that a prolyl hydroxylase 
      accounts for changes in protein level. In addition, there is evidence that HIF-1 
      is up-regulated by diverse agonists during normoxia. We investigated the impact 
      of inflammatory mediators nitric oxide (NO) and tumor necrosis factor-alpha 
      (TNF-alpha) on HIF-1alpha regulation. For comparison, LLC-PK(1) cells were 
      exposed to hypoxia, stimulated with desferroxamine (DFX, known to mimic hypoxia), 
      and the thiol-cross-linking agent phenylarsine oxide (PAO). Although all stimuli 
      elicited HIF-1alpha stabilization with differences in the time-dependent 
      accumulation pattern, significant variations appeared with regard to signaling. 
      With the use of a superoxide anion (O(2-)) generator, we established an 
      O(2-)-sensitive pathway that blocked HIF-1alpha stabilization in response to NO 
      and TNF-alpha while DFX- and PAO-evoked HIF-1alpha stabilization appeared 
      O(2-)-insensitive. NO and TNF-alpha signaling required phosphorylation events, 
      especially activation of the phosphatidylinositol 3-kinase/Akt, which is in 
      contrast to DFX and PAO. Based on HIF-1-dependent luciferase reporter gene 
      analysis, it was found that, in contrast to NO and TNF-alpha, PAO resembled a 
      stimulus that induced a dysfunctional HIF-1 complex. These data indicate that 
      diverse agonists activate HIF-1alpha under normoxic conditions by employing 
      different signaling pathways.
FAU - Sandau, K B
AU  - Sandau KB
AD  - Faculty of Biology, University of Kaiserslautern, Erwin-Schrodinger-Strasse, 
      67663 Kaiserslautern, Germany.
FAU - Zhou, J
AU  - Zhou J
FAU - Kietzmann, T
AU  - Kietzmann T
FAU - Brune, B
AU  - Brune B
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20010820
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Androstadienes)
RN  - 0 (Arsenicals)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Protein Subunits)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0HUR2WY345 (oxophenylarsine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - DH2M523P0H (Genistein)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - J06Y7MXW4D (Deferoxamine)
RN  - S88TT14065 (Oxygen)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Arsenicals/*pharmacology
MH  - Deferoxamine/*pharmacology
MH  - Genistein/pharmacology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Inflammation Mediators/*pharmacology
MH  - Kidney/blood supply
MH  - Kidney Tubules, Proximal/cytology/metabolism
MH  - Nitric Oxide/*pharmacology
MH  - Oxygen/pharmacology
MH  - Phosphorylation
MH  - *Protein Serine-Threonine Kinases
MH  - Protein Subunits
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Reactive Oxygen Species
MH  - Reperfusion Injury
MH  - Signal Transduction
MH  - Transcription Factors/*biosynthesis
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Up-Regulation
MH  - Wortmannin
EDAT- 2001/08/22 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/08/22 10:00
PHST- 2001/08/22 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/08/22 10:00 [entrez]
AID - S0021-9258(20)60045-X [pii]
AID - 10.1074/jbc.M107689200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Oct 26;276(43):39805-11. doi: 10.1074/jbc.M107689200. Epub 2001 
      Aug 20.