S-nitrosylation of heterogeneous nuclear ribonucleoprotein A/B regulates osteopontin transcription in endotoxin-stimulated murine macrophages

被引:46
作者
Gao, CJ [1 ]
Guo, HT [1 ]
Wei, JP [1 ]
Mi, ZY [1 ]
Wai, P [1 ]
Kuo, PC [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
关键词
D O I
10.1074/jbc.M313385200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Osteopontin (OPN) is a highly hydrophilic and negatively charged sialoprotein of similar to 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.
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收藏
页码:11236 / 11243
页数:8
相关论文
共 42 条
[1]   OXIDATIVE STRESS INDUCES NF-KAPPA-B DNA-BINDING AND INDUCIBLE NOS MESSENGER-RNA IN HUMAN EPITHELIAL-CELLS [J].
ADCOCK, IM ;
BROWN, CR ;
KWON, O ;
BARNES, PJ .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 199 (03) :1518-1524
[2]  
Attur MG, 2001, ARTHRITIS RHEUM-US, V44, P578, DOI 10.1002/1529-0131(200103)44:3<578::AID-ANR106>3.0.CO
[3]  
2-7
[4]  
Calmels S, 1997, CANCER RES, V57, P3365
[5]   Osteopontin activation of c-src in human melanoma cells requires the cytoplasmic domain of the integrin alpha(v)-subunit [J].
Chellaiah, M ;
Fitzgerald, C ;
Filardo, EJ ;
Cheresh, DA ;
Hruska, KA .
ENDOCRINOLOGY, 1996, 137 (06) :2432-2440
[6]   Cloning and expression of a novel dominant-negative-acting estrogen response element-binding protein in the heterogeneous nuclear ribonucleoprotein family [J].
Chen, H ;
Hu, B ;
Gacad, MA ;
Adams, JS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (47) :31352-31357
[7]   Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: A cause of vitamin D resistance [J].
Chen, H ;
Hewison, M ;
Hu, B ;
Adams, JS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (10) :6109-6114
[8]   The vitamin D response element-binding protein - A novel dominant-negative regulator of vitamin D-directed transactivation [J].
Chen, H ;
Hu, B ;
Allegretto, EA ;
Adams, JS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (45) :35557-35564
[9]   Alteration of NF-kappa B p50 DNA binding kinetics by S-nitrosylation [J].
DelaTorre, A ;
Schroeder, RA ;
Kuo, PC .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 238 (03) :703-706
[10]  
delaTorre A, 1999, J IMMUNOL, V162, P4101