Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha.

Maciejewski, Jaroslaw P.; Selleri, Carmine; Sato, Tadatsugu; Cho, Hearn J.; Keefer, Larry K.; Nathan, Carl; Young, Neal S.

doi:10.1172/jci118094

Cited by 206 publications

(123 citation statements)

References 59 publications

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“…Although it was speculated that the NO-induced suppression of hemoglobin synthesis was a result of NO-induced inhibition of heme biosynthesis (54), our current results suggest it could be the result of NO directly activating HRI present in K562 cells. In addition, activation of nitric-oxide synthase has been implicated in tamoxifen-induced apoptosis of K562 cells (56), and NO has been reported to (i) influence the growth and differentiation of normal bone marrow cells (57), (ii) induce apoptosis in bone marrow progenitor cells (58), and (iii) be a mediator of cytokineinduced hematopoietic suppression (59). Our results suggest that these effects of NO could, in part, be mediated via NOinduced activation of HRI, considering the well established role that eIF2␣ phosphorylation plays in suppressing cell growth and inducing apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

Uma

Yun

Matts

2001

Journal of Biological Chemistry

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Nitric oxide (NO) has been reported to inhibit protein synthesis in eukaryotic cells by increasing the phosphorylation of the ␣-subunit of eukaryotic initiation factor (eIF) 2. However, the mechanism through which this increase occurs has not been characterized. In this report, we examined the effect of the diffusible gases nitric oxide (NO) and carbon monoxide (CO) on the activation of the heme-regulated eIF2␣ kinase (HRI) in rabbit reticulocyte lysate. Spectral analysis indicated that both NO and CO bind to the N-terminal heme-binding domain of HRI. Although NO was a very potent activator of HRI, CO markedly suppressed NO-induced HRI activation. The NO-induced activation of HRI was transduced through the interaction of NO with the N-terminal heme-binding domain of HRI and not through S-nitrosylation of HRI. We postulate that the regulation of HRI activity by diffusible gases may be of wider physiological significance, as we further demonstrate that NO generators increase eIF2␣ phosphorylation levels in NT2 neuroepithelial and C2C12 myoblast cells and activate HRI immunoadsorbed from extracts of these non-erythroid cell lines.Over 2 decades ago, the heme-regulated inhibitor (HRI) 1 of protein chain initiation in rabbit reticulocyte lysate (RRL) was identified as a heme-regulated protein kinase that phosphorylated the ␣-subunit of eukaryotic initiation factor eIF2 (reviewed in Refs. 1-3). eIF2 delivers Met-tRNA i in a complex with GTP to 43 S ribosomal initiation complexes and is released as a complex with GDP at the completion of the initiation cycle. Recycling of eIF2⅐GDP and the formation of eIF2⅐GTP⅐Met-tRNA i complexes requires the action of the guanine nucleotide exchange factor, eIF2B. Under heme-deficient conditions, HRI is activated and phosphorylates eIF2. Phosphorylated eIF2 avidly binds eIF2B, sequestering eIF2B in a poorly dissociable complex, which subsequently leads to the inhibition of the initiation of translation, as eIF2⅐GDP complexes that are present in excess of eIF2B fail to recycle. Thus, HRI functions to coordinate globin synthesis with heme availability in RRL.The amino acid sequence deduced from HRI cDNA indicates that it is composed of at least five distinct domains (4). The unique N-terminal domain of HRI contains ϳ165 amino acids. The second and fourth domains contain conserved sequence motifs I-V and motifs VI-XI, which comprise the N-terminal and C-terminal catalytic lobes of protein kinases, respectively. The third and fifth domains are also unique, consisting of ϳ140 amino acids that are inserted between the two conserved kinase lobes and ϳ50 amino acids at the C terminus, respectively.HRI is a hemoprotein that contains two distinct of hemebinding sites (5-7). Heme binding to the first site is stable, and remains associated with purified HRI, whereas heme-binding to the second site is reversible and appears to be responsible for the rapid heme-induced down-regulation of HRI activity . We have recently demonstrated that the N-terminal domain of HRI contains the stable heme-binding...

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Section: Discussionmentioning

confidence: 99%

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

Uma

Yun

Matts

2001

Journal of Biological Chemistry

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“…NOS appears to inhibit Fasinduced caspase activation and PARP cleavage without altering levels of Fas expression. Although studies have shown that NO or related molecules can exert either pro-or anti-apoptotic effects depending on the cell type and stimulus (39,(43)(44)(45)(46)(47)(48)(49), the emerging picture is one where the predominant physiologic effect of NOS is inhibition of apoptosis. For instance, NO inhibits apoptosis in murine splenic B cells, human B cell lines, rat ovarian follicles, and human eosinophils (39,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Inhibits Fas-induced Apoptosis

Mannick¹,

Miao²,

Stamler³

1997

Journal of Biological Chemistry

298

168

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“…IFNs are a family of multifunctional cytokines that trigger immunomodulatory, antiviral, antiproliferative, and antitumor activities (Deiss et al, 1995;Maciejewski et al, 1995;De Maeyer and De MaeyerGuignard, 1998). IFN-g induces p53-independent apoptosis and cell cycle arrest (Ossina et al, 1997;Kano et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-γ induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression

et al. 2003

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Constitutive activation of the telomerase is a key step in the development of human cancers. Interferon-c (IFN-c) signaling induces growth arrest in many tumors through multiple regulatory mechanisms. In this study, we show that IFN-c signaling represses telomerase activity and human telomerase reverse transcriptase (hTERT) transcription, and suggest that this signaling is mediated by IRF-1. Ectopic expression of IRF-1 attenuated hTERT promoter activity. Murine embryonic fibroblasts (MEFs) genetically deficient in IRF-1 (IRF-1 À/À ) showed an elevated level (>15 times) of hTERT promoter activity as compared to the hTERT promoter activity of wild-type MEFs. The telomerase activity and hTERT expression in IRF-1 À/À MEFs were downregulated by IRF-1 transfection. Interestingly, less extent of telomerase repression was observed in HPV E6 and E7 negative, p53 mutant HT-3 cells than in HPV 18 E6 and E7 positive HeLa cells (intact p53). These findings provide evidence that IRF-1 is a potential mediator of IFN-c-induced attenuation of telomerase activity and hTERT expression.

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Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha.

Cited by 206 publications

References 59 publications

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

Nitric Oxide Inhibits Fas-induced Apoptosis

Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-γ induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression

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