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Originally published In Press as doi:10.1074/jbc.M211051200 on April 16, 2003
J. Biol. Chem., Vol. 278, Issue 27, 24359-24370, July 4, 2003
Basal Expression of I B Is Controlled by the Mammalian Transcriptional Repressor RBP-J (CBF1) and Its Activator Notch1*
Fiona Oakley   ,
Jelena Mann ,
Richard G. Ruddell ,
Jessica Pickford ,
Gerry Weinmaster ¶ and
Derek A. Mann ||
From the
Liver Group, Division of Infection, Inflammation and Repair, University of Southampton, Southampton SO16 6YD, United Kingdom and the ¶Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, California 90095-1737
By using the hepatic stellate cell (HSC) as a paradigm for cells that undergo long term re-programming of NF- B-dependent transcription, we have determined a novel mechanism by which mammalian cells establish their basal NF-B activity. Elevation of NF-B activity during HSC activation is accompanied by induction of CBF1 expression and DNA binding activity. We show that the transcriptional repressor CBF1 interacts with a dual NF-B/CBF1-binding site (B2) in the IB promoter. Nucleotide substitutions that disrupt CBF1 binding to the B2 site result in an elevation of IB promoter activity and loss of responsiveness of the promoter to a transfected CBF1 reporter vector. Overexpression of CBF1 in COS1 cells was associated with markedly reduced IB protein expression and elevated NF-B DNA binding activity. CBF1-induced repression of IB promoter activity was reversed in HSC transfected with the Notch1 intracellular domain (NICD). The ability of NICD to enhance IB gene transcription was confirmed in COS1 cells and was found to be dependent on an intact RAM domain of NICD that has been shown previously to help mediate the interaction of NICD with CBF1. One of the mechanisms by which NICD is thought to convert CBF1 into an activator of transcription is via the recruitment of transcriptional co-activators/histone acetylases to gene promoters. Co-transfection of HSC with NICD and p53 caused a diminution of IB promoter activity, by contrast overexpression of p300 enhanced IB promoter function. Taken together, these data suggest that basal IB expression (and as a consequence NF-B activity) is under the control of the various components of the CBF1/Notch signal transduction pathway.
Received for publication, October 29, 2003
, and in revised form, April 7, 2003.
* This work was supported by UK Medical Research Council Grants G9900951 and G9900297 (to D. A. M.) and the Wellcome Trust Grant 068524/Z/02/Z. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
 Both authors contributed equally to this work.
|| To whom correspondence should be addressed: Liver Group, Division of Infection, Inflammation and Repair, University of Southampton, Level D, Southampton General Hospital, Southampton SO16 6YD UK. Tel.: 44 2380796871; Fax: 44 2380794154; E-mail: dam2{at}soton.ac.uk.
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