Tumor suppressor SMAR1 represses IkappaBalpha expression and inhibits p65 transactivation through matrix attachment regions.

Aberrant NF-kappaB activity promotes tumorigenesis. However, NF-kappaB also inhibits tumor growth where tumor suppressor pathways remain unaltered. Thus, its role in tumorigenesis depends upon the function of other cellular factors. Tumor suppressor SMAR1 down-modulated in high grade breast cancers is regulated by p53 and is reported to interact and stabilize ...
p53. Because both SMAR1 and NF-kappaB are involved in tumorigenesis, we investigated the effect of SMAR1 upon NF-kappaB activity. We show that SMAR1 induction by doxorubicin or overexpression produces functional NF-kappaB complexes that are competent for binding to NF-kappaB consensus sequence. However, SMAR1 induced p65-p50 complex is phosphorylation- and transactivation-deficient. Induction of functional NF-kappaB complexes stems from down-regulation of IkappaBalpha transcription through direct binding of SMAR1 to the matrix attachment region site present in IkappaBalpha promoter and recruitment of corepressor complex. Real time PCR array for NF-kappaB target genes revealed that SMAR1 down-regulates a subset of NF-kappaB target genes that are involved in tumorigenesis. We also show that SMAR1 inhibits tumor necrosis factor alpha-induced induction of NF-kappaB suggesting that activation of NF-kappaB by SMAR1 is independent and different from classical pathway. Thus, for the first time we report that a tumor suppressor protein SMAR1 can modulate NF-kappaB transactivation and inhibit tumorigenesis by regulating NF-kappaB target genes.
Mesh Terms:
Animals, Binding Sites, Cell Cycle Proteins, Cell Line, Tumor, DNA, DNA-Binding Proteins, Down-Regulation, Histone Deacetylase 1, Histone Deacetylases, Humans, I-kappa B Kinase, Mice, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Protein Multimerization, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation, Tumor Necrosis Factor-alpha
J. Biol. Chem.
Date: Jan. 09, 2009
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