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J. Biol. Chem., Vol. 279, Issue 12, 11236-11243, March 19, 2004

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S-Nitrosylation of Heterogeneous Nuclear Ribonucleoprotein A/B Regulates Osteopontin Transcription in Endotoxin-stimulated Murine Macrophages^*

Chengjiang Gao, Hongtao Guo, Junping Wei, Zhiyong Mi, Philip Wai, and Paul C. Kuo

From the Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710

Osteopontin (OPN) is a highly hydrophilic and negatively charged sialoprotein of 298 amino acids that contains a Gly-Arg-Gly-Asp-Ser sequence. It is a secreted protein with diverse regulatory functions, including cell adhesion and migration, tumor growth and metastasis, atherosclerosis, aortic valve calcification, and repair of myocardial injury. Despite the many recognized functions of OPN, very little is known of the transcriptional regulation of OPN. In this regard, we have previously demonstrated that OPN transcription and promoter activity are significantly up-regulated in response to NO in a system of endotoxin-stimulated murine macrophages. However, the specific cis- and trans-regulatory elements that determine the extent of endotoxin- and NO-mediated induction of OPN synthesis are unknown. In this follow-up study, we demonstrate that: 1) OPN gene transcription is regulated by a constitutive transcriptional repressor protein, heterogeneous nuclear ribonucleoprotein A/B (hnRNP A/B); 2) inhibition of in vivo hnRNP DNA binding activity is accompanied by increased S-nitrosylation of hnRNP A/B in the setting of lipopolysaccharide (LPS)-mediated NO synthesis; 3) inhibition of LPS mediated NO synthesis restores hnRNP DNA binding and decreases the extent of S-nitrosylation; and 4) S-nitrosylation of hnRNP at cysteine 104 inhibits in vitro DNA binding activity, which is reversed by dithiothreitol. Our findings suggest that LPS induced S-nitrosylation of hnRNP inhibits its activity as a constitutive repressor of the OPN promoter and results in enhanced OPN expression.

Received for publication, December 8, 2003 , and in revised form, January 8, 2004.

^* This work was supported by the American College of Surgeons Clowes Faculty Development Award (to P. C. K.) and National Institutes of Health Grants R01 AI44629 (to P. C. K.) and R01 GM65113 (to P. C. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 110 Bell Bldg., Box 3522, DUMC, Durham, NC 27710. Tel.: 919-969-9810; Fax: 919-684-8716; E-mail: kuo00004{at}mc.duke.edu.

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