Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia

Sogawa, Kazuhiro; Numayama-Tsuruta, Keiko; Ema, Masatsugu; Abe, Manabu; Abe, Haruo; Fujii‐Kuriyama, Yoshiaki

doi:10.1073/pnas.95.13.7368

Cited by 212 publications

(133 citation statements)

References 52 publications

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“…2, lanes 5, 7, and 9). These results with SNP are consistent with those of Sogawa et al (32), who tested a hypoxia-inducible reporter gene with SNP and two other NO donors.…”

Section: Effect Of Carbon Monoxide and Nitric Oxide On The Induction supporting

confidence: 82%

“…The hypoxic induction of erythropoietin (27), vascular endothelial growth factor (28,29), and other genes (30) was markedly blunted in the presence of carbon monoxide (CO), a molecule whose only established biological function is binding to ferrous atoms on heme groups. Subquently, another heme ligand, nitric oxide (NO), was shown to exert a similar effect (29,31,32). In addition to hypoxia, HIF-1 can be activated by the transition metal Co 2ϩ as well as by iron chelation (33).…”

mentioning

confidence: 99%

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Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide

Huang¹,

Willmore²,

et al. 1999

Journal of Biological Chemistry

288

180

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It has been proposed that cells sense hypoxia by a heme protein, which transmits a signal that activates the heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1), thereby inducing a number of physiologically relevant genes such as erythropoietin (Epo). We have investigated the mechanism by which two heme-binding ligands, carbon monoxide and nitric oxide, affect oxygen sensing and signaling. Two concentrations of CO (10 and 80%) suppressed the activation of HIF-1 and induction of Epo mRNA by hypoxia in a dosedependent manner. In contrast, CO had no effect on the induction of HIF-1 activity and Epo expression by either cobalt chloride or the iron chelator desferrioxamine. The affinity of CO for the putative sensor was much lower than that of oxygen (Haldane coefficient, ϳ0.5). Parallel experiments were done with 100 M sodium nitroprusside, a nitric oxide donor. Both NO and CO inhibited HIF-1 DNA binding by abrogating hypoxiainduced accumulation of HIF-1␣ protein. Moreover, both NO and CO specifically targeted the internal oxygendependent degradation domain of HIF-1␣, and also repressed the C-terminal transactivation domain of HIF-1␣. Thus, NO and CO act proximally, presumably as heme ligands binding to the oxygen sensor, whereas desferrioxamine and perhaps cobalt appear to act at a site downstream.

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“…2, lanes 5, 7, and 9). These results with SNP are consistent with those of Sogawa et al (32), who tested a hypoxia-inducible reporter gene with SNP and two other NO donors.…”

Section: Effect Of Carbon Monoxide and Nitric Oxide On The Induction supporting

confidence: 82%

mentioning

confidence: 99%

Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide

Huang¹,

Willmore²,

et al. 1999

Journal of Biological Chemistry

288

180

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“…We cannot exclude, however, that a chemical reaction of NO or one of its metabolites with PHD causes enzyme inactivation at a moiety other than Fe 2ϩ . A number of reports from independent groups suggested that treatment of cells with NO donors under hypoxic conditions inhibited HIF-1␣ accumulation and transactivation of HIF-1 (Liu et al, 1998;Sogawa et al, 1998;Huang et al, 1999). At present we do not have an explanation for the difference between normoxic and hypoxic NO effects.…”

Section: Discussionmentioning

confidence: 56%

“…Regulation of HIF-1 activity by NO is likely to be of (patho)-physiological relevance but molecular mechanisms have not been defined yet. Initial observations suggested that NO inhibits hypoxia-induced HIF-1␣ stabilization and HIF-1 transcriptional activation (Liu et al, 1998;Sogawa et al, 1998;Huang et al, 1999). More recent studies indicated that chemically diverse NO donors or enhanced endogenous NO formation by inducible NO-synthase or NO formation in a coculture system under normoxic conditions provoked HIF-1␣ stabilization, HIF-1 DNA-binding, and activation of downstream target gene expression (Kimura et al, 2001;Sandau et al, 2001aSandau et al, , 2001bZhou et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases

Metzen

Zhou

Jelkmann

et al. 2003

MBoC

379

261

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Hypoxia inducible factor-1 (HIF-1) is the master regulator of metabolic adaptation to hypoxia. It is appreciated that HIF-1␣ accumulation is achieved under normoxic conditions by e.g., nitric oxide. We determined molecular mechanisms of HIF-1␣ accumulation under the impact of S-nitrosoglutathione (GSNO). In human embryonic kidney cells GSNO provoked nuclear accumulation of HIF-1␣. This appeared unrelated to gene transcription and protein translation, thus pointing to inhibition of HIF-1␣ degradation. Indeed, GSNO as well as the hypoxia mimic CoCl 2 decreased ubiquitination of HIF-1␣ and GSNO-induced HIF-1␣ failed to coimmunoprecipitate with pVHL (von Hippel Lindau protein). Considering that HIF-1␣-pVHL interactions require prolyl hydroxylation of HIF-1␣, we went on to demonstrate inhibition of HIF-1␣ prolyl hydroxylases (PHDs) by GSNO. In vitro HIF-1␣-pVHL interactions revealed that GSNO dose-dependently inhibits PHD activity but not the interaction of a synthetic peptide resembling the hydroxylated oxygen-dependent degradation domain of HIF-1␣ with pVHL. We conclude that GSNO-attenuated prolyl hydroxylase activity accounts for HIF-1␣ accumulation under conditions of NO formation during normoxia and that PHD activity is subject to regulation by NO. INTRODUCTIONThe heterodimeric transcription factor hypoxia inducible factor-1 (HIF-1) plays a central role in adaptation to decreased oxygen availability (Semenza, 2002;Wenger, 2002;Brü ne and Zhou, 2003). HIF-1 is composed of the two basic helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator (ARNT), also known as HIF-1␤ (Wang and Semenza, 1995). In many cell types, the mRNA of both HIF-1␣ and HIF-1␤ appear permanently expressed and HIF-1␤ protein is constitutively present. However, HIF-1␣ protein is kept at a low or undetectable level under normoxia. In hypoxia, HIF-1␣ is strikingly induced, translocates to the nucleus, and dimerizes with HIF-1␤ to form HIF-1, which binds to hypoxiaresponsive elements (HRE) in regulatory regions of an impressive array of target genes involved in angiogenesis, erythropoiesis, vasomotor control, and energy metabolism as well as in cell survival decisions (for references, see Maxwell et al., 2001;Wenger, 2002; Zhu et al., 2002). This makes HIF-1 the master regulator of oxygen homeostasis to meet cell and tissue requirements in a situation of oxygen deficiency.In normoxia HIF-1␣ is bound to the von Hippel Lindau protein (pVHL) (Maxwell et al., 1999;Hon et al., 2002;Min et al., 2002), which is the substrate recognizing component of an E3 ubiquitin ligase complex (Cockman et al., 2000;Ohh et al., 2000;Tanimoto et al., 2000). Consequently, HIF-1␣ is polyubiquitinated and degraded by the 26S proteasome system, thus accounting for its low normoxic level of expression (Salceda and Caro, 1997;Huang et al., 1998;Kallio et al., 1999). The requirement of pVHL for HIF-1␣ degradation is underscored in cells that do not contain a functional pVHL, which leads to high levels of HIF-1␣ in normox...

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“…20 The results showed that SIN-1 at 500 mM inhibited cell proliferation to a much greater extent than did CoCl 2 at 50 mM, while SIN-1 treatment alone or in combination with 50 mM CoCl 2 did not induce cell death (Figure 7b …”

Section: -Morpholinosydnonimine Inhibited Hif-1a Accumulation and Hrmentioning

confidence: 94%

Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of hypoxia-inducible factor-1α

Huang¹,

et al. 2003

Leukemia

101

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Cellular and systemic O 2 concentrations are tightly regulated to maintain delicate oxygen homeostasis. Although the roles of hypoxia in solid tumors have been widely studied, few studies were reported regarding the possible effects of hypoxia on leukemic cells. Here, we showed for the first time that low concentrations of cobalt chloride (CoCl 2 ), a hypoxia-mimicking agent, and 2-3% O 2 triggered differentiation of various subtypes of human acute myeloid leukemic (AML) cell lines, including NB4, U937 and Kasumi-1 cells, respectively, from M3, M5 and M2b-type AML, but CoCl 2 did not modulate AML subtype-specific fusion proteins promyelocytic leukemia-retinoic acid receptor alpha (PML-RARa) and AML1-ETO. Treatment with CoCl 2 also induced primary leukemic cells from some AML patients to undergo differentiation. Similar to what occurs in solid tumor cells, CoCl 2 -mimicked hypoxia also increased the level of hypoxia-inducible factor (HIF)-1a protein and its DNAbinding activity in leukemic cells. The CoCl 2 induction of HIF-1a protein and its DNA-binding activity were inhibited by 3-morpholinosydnonimine, which also blocked CoCl 2 -induced cell differentiation in leukemic cells. These results provide an insight into a possible link of hypoxia or HIF-1a and leukemic cell differentiation, and are possibly of significance to explore clinical potentials of hypoxia or hypoxia-mimicking agents and novel target-based drugs for differentiation therapy of leukemia

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Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia

Cited by 212 publications

References 52 publications

Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide

Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide

Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases

Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of hypoxia-inducible factor-1α

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