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J. Biol. Chem., Vol. 278, Issue 32, 29776-29782, August 8, 2003

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Regulation of c-myc Gene by Nitric Oxide via Inactivating NF-B Complex in P19 Mouse Embryonal Carcinoma Cells^*

Sung Wook Park and Li-Na Wei 

From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Nitric oxide (NO) may regulate gene expression by directly modifying redox state-sensitive residues of transcription factors. Here we show that the NO donor, sodium nitroprusside (SNP), rapidly represses c-myc gene transcription in a protein synthesis-independent manner in P19 embryonal carcinoma cells by inactivation of NF-B. SNP treatment reduces the DNA binding ability of the constitutively active NF-B heterodimer, p65/p50, and its consequent transactivation of the c-myc promoter. Repression can be blocked by the peroxynitrite scavenger, deferoxamine, but not by dithiothreitol, which triggers reduction of S-nitrosylated residues. In HEK293 cells, where tumor necrosis factor- can activate NF-B, SNP likewise suppresses the binding of the active NF-B complex, restoring the binding of the repressive p50/p50 homodimer complex. This effect of SNP in HEK293 cells is also blocked by deferoxamine. Chromatin immunoprecipitation analysis of SNP-treated P19 cells reveals reduced association of p65, but not of p50, with the promoter region of the endogenous c-myc gene. SNP-induced p65 dissociation was associated with the recruitment of histone deacetylase 1 and 2 to the endogenous c-myc gene promoter and the subsequent deacetylation of its chromatin histone. This study is the first to demonstrate that NO modulates the transcriptional activity of the c-myc gene promoter by dissociating the active form of NF-B and replacing it with a repressive NF-B complex, correlated with the recruitment of gene-silencing histone deacetylases. In light of findings that NF-B stimulates Myc oncoprotein expression in cancers, our findings suggest that NO should be investigated as a prospective therapeutic cancer agent.

Received for publication, March 31, 2003 , and in revised form, May 8, 2003.

^* This study was supported by National Institutes of Health Grants DA11190, DA11806, DA13926, DK 54733, and DK60521 (to L.-N. W.). 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: Dept. of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455. Tel.: 612-625-9402; Fax: 612-625-8408, E-mail: weixx009{at}tc.umn.edu.

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