In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 6 ( 2007-03-15), p. 2747-2756
Abstract:
Mullerian-inhibiting substance (MIS), a transforming growth factor-β family member, activates the nuclear factor-κB (NF-κB) pathway and induces the expression of B-cell translocation gene 2 (BTG2), IFN regulatory factor-1 (IRF-1), and the chemokine Gro-β. Inhibiting NF-κB activation with a phosphorylation-deficient IκBα mutant abrogated MIS-mediated induction of all three genes. Expression of dominant-negative Smad1, in which serines at the COOH-terminal SSVS motif are converted to alanines, suppressed MIS-induced Smad1 phosphorylation and impaired MIS-stimulated Gro-β promoter-driven reporter expression and Gro-β mRNA. Suppressing Smad1 expression using small interfering RNA also mitigated MIS-induced Gro-β mRNA, suggesting that regulation of Gro-β expression by MIS was dependent on activation of NF-κB as well as Smad1. However, induction of IRF-1 and BTG2 mRNAs by MIS was independent of Smad1 activation. Characterization of κB-binding sequences within Gro-β, BTG2, and IRF-1 promoters showed that MIS stimulated binding of p50 and p65 subunits to all three sites, whereas phosphorylated Smad1 (phospho-Smad1) protein was detectable only in the NF-κB complex bound to the κB site of the Gro-β promoter. Consistent with these observations, chromatin immunoprecipitation assays showed recruitment of both phospho-Smad1 and p65 to the Gro-β promoter in vivo, whereas p65, but not phospho-Smad1, was recruited to the BTG2 promoter. These results show a novel interaction between MIS-stimulated Smad1 and NF-κB signaling in which enhancement of NF-κB DNA binding and gene expression by phospho-Smad1 is dependent on the sequence of the κB consensus site within the promoter. [Cancer Res 2007;67(6):2747–56]
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-06-2312
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2007
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
