Nitric Oxide-induced Cellular Stress and P53 Activation in Chronic Inflammation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Jan 9

PMID 12518062

Citations 110

Authors

Lorne J Hofseth

Shinichi Saito

S Perwez Hussain

Michael G Espey

Katrina M Miranda

Yuzuru Araki

Chamelli Jhappan

Yuichiro Higashimoto

Peijun He

Steven P Linke

Martha M Quezado

Irit Zurer

Varda Rotter

David A Wink

Ettore Appella

Curtis C Harris

Affiliations

Soon will be listed here.

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.

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