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Nitric oxide-induced cellular stress and p53 activation in chronic inflammation.

ABSTRACT: Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G(2)M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21(WAF1) was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation.

SUBMITTER: Hofseth LJ

PROVIDER: S-EPMC140909 | biostudies-literature | 2003 Jan

REPOSITORIES: biostudies-literature

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Nitric oxide-induced cellular stress and p53 activation in chronic inflammation.

Hofseth Lorne J LJ Saito Shin'ichi S Hussain S Perwez SP Espey Michael G MG Miranda Katrina M KM Araki Yuzuru Y Jhappan Chamelli C Higashimoto Yuichiro Y He Peijun P Linke Steven P SP Quezado Martha M MM Zurer Irit I Rotter Varda V Wink David A DA Appella Ettore E Harris Curtis C CC

Proceedings of the National Academy of Sciences of the United States of America 20021223 1

Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G(2)M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing m ...[more]

PMID: 12518062

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Project description:BACKGROUND:Nutrition with ammonium (NH4+) can enhance the drought tolerance of rice seedlings in comparison to nutrition with nitrate (NO3-). However, there are still no detailed studies investigating the response of nitric oxide (NO) to the different nitrogen nutrition and water regimes. To study the intrinsic mechanism underpinning this relationship, the time-dependent production of NO and its protective role in the antioxidant defense system of NH4+- or NO3--supplied rice seedlings were studied under water stress. RESULTS:An early NO burst was induced by 3?h of water stress in the roots of seedlings subjected to NH4+ treatment, but this phenomenon was not observed under NO3- treatment. Root oxidative damage induced by water stress was significantly higher for treatment with NO3- than with NH4+ due to reactive oxygen species (ROS) accumulation in the former. Inducing NO production by applying the NO donor 3?h after NO3- treatment alleviated the oxidative damage, while inhibiting the early NO burst by applying the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO) increased root oxidative damage in NH4+ treatment. Application of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester(L-NAME) completely suppressed NO synthesis in roots 3?h after NH4+ treatment and aggravated water stress-induced oxidative damage. Therefore, the aggravation of oxidative damage by L-NAME might have resulted from changes in the NOS-mediated early NO burst. Water stress also increased the activity of root antioxidant enzymes (catalase, superoxide dismutase, and ascorbate peroxidase). These were further induced by the NO donor but repressed by the NO scavenger and NOS inhibitor in NH4+-treated roots. CONCLUSION:These findings demonstrate that the NOS-mediated early NO burst plays an important role in alleviating oxidative damage induced by water stress by enhancing the antioxidant defenses in roots supplemented with NH4+.

Project description:OBJECTIVE:Impaired endothelial cell (EC) autophagy compromises shear stress-induced nitric oxide (NO) generation. We determined the responsible mechanism. APPROACH AND RESULTS:On autophagy compromise in bovine aortic ECs exposed to shear stress, a decrease in glucose uptake and EC glycolysis attenuated ATP production. We hypothesized that decreased glycolysis-dependent purinergic signaling via P2Y1 (P2Y purinoceptor 1) receptors, secondary to impaired autophagy in ECs, prevents shear-induced phosphorylation of eNOS (endothelial nitric oxide synthase) at its positive regulatory site S1117 (p-eNOSS1177) and NO generation. Maneuvers that restore glucose transport and glycolysis (eg, overexpression of GLUT1 [glucose transporter 1]) or purinergic signaling (eg, addition of exogenous ADP) rescue shear-induced p-eNOSS1177 and NO production in ECs with impaired autophagy. Conversely, inhibiting glucose transport via GLUT1 small interfering RNA, blocking purinergic signaling via ectonucleotidase-mediated ATP/ADP degradation (eg, apyrase), or inhibiting P2Y1 receptors using pharmacological (eg, MRS2179 [2'-deoxy-N6-methyladenosine 3',5'-bisphosphate tetrasodium salt]) or genetic (eg, P2Y1-receptor small interfering RNA) procedures inhibit shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Supporting a central role for PKC?T505 (protein kinase C delta T505) in relaying the autophagy-dependent purinergic-mediated signal to eNOS, we find that (1) shear stress-induced activating phosphorylation of PKC?T505 is negated by inhibiting autophagy, (2) shear-induced p-eNOSS1177 and NO generation are restored in autophagy-impaired ECs via pharmacological (eg, bryostatin) or genetic (eg, constitutively active PKC?) activation of PKC?T505, and (3) pharmacological (eg, rottlerin) and genetic (eg, PKC? small interfering RNA) PKC? inhibition prevents shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Key nodes of dysregulation in this pathway on autophagy compromise were revealed in human arterial ECs. CONCLUSIONS:Targeted reactivation of purinergic signaling and PKC? has strategic potential to restore compromised NO generation in pathologies associated with suppressed EC autophagy.

Dataset Information

Nitric oxide-induced cellular stress and p53 activation in chronic inflammation.

Publications

Nitric oxide-induced cellular stress and p53 activation in chronic inflammation.

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