PMID- 14531732
OWN - NLM
STAT- MEDLINE
DCOM- 20031202
LR  - 20181113
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 376
IP  - Pt 2
DP  - 2003 Dec 1
TI  - Regulation of hypoxia-inducible factor-1alpha by nitric oxide through 
      mitochondria-dependent and -independent pathways.
PG  - 537-44
AB  - Nitric oxide (NO) has been reported both to promote and to inhibit the activity 
      of the transcription factor hypoxia-inducible factor-1 (HIF-1). In order to avoid 
      the pitfalls associated with the use of NO donors, we have developed a human cell 
      line (Tet-iNOS 293) that expresses the inducible NO synthase (iNOS) under the 
      control of a tetracycline-inducible promoter. Using this system to generate 
      finely controlled amounts of NO, we have demonstrated that the stability of the 
      alpha-subunit of HIF-1 is regulated by NO through two separate mechanisms, only 
      one of which is dependent on a functional respiratory chain. HIF-1alpha is 
      unstable in cells maintained at 21% O(2), but is progressively stabilized as the 
      O(2) concentration decreases, resulting in augmented HIF-1 DNA-binding activity. 
      High concentrations of NO (>1 microM) stabilize HIF-1alpha at all O(2) 
      concentrations tested. This effect does not involve the respiratory chain, since 
      it is preserved in cells lacking functional mitochondria (rho(0)-cells) and is 
      not reproduced by other inhibitors of the cytochrome c oxidase. By contrast, 
      lower concentrations of NO (<400 nM) cause a rapid decrease in HIF-1alpha 
      stabilized by exposure of the cells to 3% O(2). This effect of NO is dependent on 
      the inhibition of mitochondrial respiration, since it is mimicked by other 
      inhibitors of mitochondrial respiration, including those not acting at cytochrome 
      c oxidase. We suggest that, although stabilization of HIF-1alpha by high 
      concentrations of NO might have implications in pathophysiological processes, the 
      inhibitory effect of lower NO concentrations is likely to be of physiological 
      relevance.
FAU - Mateo, Jesus
AU  - Mateo J
AD  - Fundacion Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 
      C/Sinesio Delgado 4, 28029 Madrid, Spain. jmateo@cnic.es
FAU - Garcia-Lecea, Marta
AU  - Garcia-Lecea M
FAU - Cadenas, Susana
AU  - Cadenas S
FAU - Hernandez, Carlos
AU  - Hernandez C
FAU - Moncada, Salvador
AU  - Moncada S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Transcription Factors)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (NOS2 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - S88TT14065 (Oxygen)
SB  - IM
CIN - Biochem J. 2003 Dec 1;376(Pt 2):e5-6. PMID: 14627433
MH  - Cell Hypoxia
MH  - Cell Line
MH  - Cell Respiration
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Mitochondria/*metabolism/physiology
MH  - Nitric Oxide/biosynthesis/*physiology
MH  - Nitric Oxide Synthase/metabolism
MH  - Nitric Oxide Synthase Type II
MH  - Oxygen/pharmacology
MH  - Signal Transduction
MH  - Transcription Factors/*metabolism
PMC - PMC1223794
EDAT- 2003/10/09 05:00
MHDA- 2003/12/03 05:00
PMCR- 2004/06/01
CRDT- 2003/10/09 05:00
PHST- 2003/10/08 00:00 [accepted]
PHST- 2003/10/03 00:00 [revised]
PHST- 2003/07/30 00:00 [received]
PHST- 2003/10/09 05:00 [pubmed]
PHST- 2003/12/03 05:00 [medline]
PHST- 2003/10/09 05:00 [entrez]
PHST- 2004/06/01 00:00 [pmc-release]
AID - BJ20031155 [pii]
AID - 10.1042/BJ20031155 [doi]
PST - ppublish
SO  - Biochem J. 2003 Dec 1;376(Pt 2):537-44. doi: 10.1042/BJ20031155.