title: Tumor suppressor SMAR1 represses IkappaBalpha expression and inhibits p65 transactivation through matrix attachment regions.
abstract: 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.
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, Maharastra, India.
authors.forename: Kamini
authors.initials: K
authors.lastname: Singh
authors.forename: Surajit
authors.initials: S
authors.lastname: Sinha
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Malonia
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bist
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.forename: Samit
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C417914:BANP protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D051550:I-kappa B Kinase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases