TY - JOUR
T1 - Tumor suppressor SMAR1 represses IκBαl expression and inhibits p65 transactivation through matrix attachment regions
AU - Singh, Kamini
AU - Sinha, Surajit
AU - Malonia, Sunil Kumar
AU - Bist, Pradeep
AU - Tergaonkar, Vinay
AU - Chattopadhyay, Samit
PY - 2009/1/9
Y1 - 2009/1/9
N2 - Aberrant NF-κB activity promotes tumorigenesis. However, NF-κB 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-κB are involved in tumorigenesis, we investigated the effect of SMAR1 upon NF-κB activity. We show that SMAR1 induction by doxorubicin or overexpression produces functional NF-κB complexes that are competent for binding to NF-κB consensus sequence. However, SMAR1 induced p65-p50 complex is phosphorylation- and transactiva-tion-deficient. Induction of functional NF-κB complexes stems from down-regulation of IκBα transcription through direct binding of SMAR1 to the matrix attachment region site present in IκBalpha; promoter and recruitment of corepressor complex. Real time PCR array for NF-κB target genes revealed that SMAR1 down-regulates a subset of NF-κB target genes that are involved in tumorigenesis. We also show that SMAR1 inhibits tumor necrosis factor α-induced induction of NF-κB suggesting that activation of NF-κB 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-κB trans-activation and inhibit tumorigenesis by regulating NF-κB target genes.
AB - Aberrant NF-κB activity promotes tumorigenesis. However, NF-κB 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-κB are involved in tumorigenesis, we investigated the effect of SMAR1 upon NF-κB activity. We show that SMAR1 induction by doxorubicin or overexpression produces functional NF-κB complexes that are competent for binding to NF-κB consensus sequence. However, SMAR1 induced p65-p50 complex is phosphorylation- and transactiva-tion-deficient. Induction of functional NF-κB complexes stems from down-regulation of IκBα transcription through direct binding of SMAR1 to the matrix attachment region site present in IκBalpha; promoter and recruitment of corepressor complex. Real time PCR array for NF-κB target genes revealed that SMAR1 down-regulates a subset of NF-κB target genes that are involved in tumorigenesis. We also show that SMAR1 inhibits tumor necrosis factor α-induced induction of NF-κB suggesting that activation of NF-κB 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-κB trans-activation and inhibit tumorigenesis by regulating NF-κB target genes.
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U2 - 10.1074/jbc.M801088200
DO - 10.1074/jbc.M801088200
M3 - Article
C2 - 18981184
AN - SCOPUS:59449090454
SN - 0021-9258
VL - 284
SP - 1267
EP - 1278
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -