Regulation of c-myc gene by nitric oxide via inactivating NF-κB complex in P19 mouse embryonal carcinoma cells

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Abstract

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-κB. SNP treatment reduces the DNA binding ability of the constitutively active NF-κB 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-α can activate NF-κB, SNP likewise suppresses the binding of the active NF-κB 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-κB and replacing it with a repressive NF-κB complex, correlated with the recruitment of gene-silencing histone deacetylases. In light of findings that NF-κB stimulates Myc oncoprotein expression in cancers, our findings suggest that NO should be investigated as a prospective therapeutic cancer agent.

Original languageEnglish (US)
Pages (from-to)29776-29782
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number32
DOIs
StatePublished - Aug 8 2003

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