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J. Biol. Chem., Vol. 282, Issue 11, 8424-8434, March 16, 2007

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Regulation of NF-B-dependent Gene Expression by the POU Domain Transcription Factor Oct-1^*

Nathaniel G. dela Paz¹, Simos Simeonidis², Christopher Leo³, David W. Rose^¶4, and Tucker Collins⁴⁵

From the Molecular Pathology Graduate Program, School of Medicine, University of California, San Diego, La Jolla, California 92093-0673, the Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, the ^¶Department of Medicine and University of California San Diego Cancer Center, University of California, San Diego, La Jolla, California 92093-0673

Maintenance of the cells of the vessel wall in a quiescent state is an important aspect of normal vascular physiology. Transcriptional repressors are widely believed to regulate this process, yet the exact factors involved and the mechanism of repression are not known. Here, we report that the POU domain transcription factor Oct-1 represses the expression of E-selectin and vascular cell adhesion molecule (VCAM-1), two cytokine-inducible, NF-B-dependent endothelial-leukocyte adhesion molecules that participate in the leukocyte recruitment phase of the inflammatory response. Co-transfection and microinjection studies demonstrate that Oct-1 blocks tumor necrosis factor -stimulated E-selectin and VCAM-1 expression. Gene expression arrays indicate that control of tumor necrosis factor -induced, NF-B-dependent gene expression by Oct-1 is promoter-specific. A DNA-binding mutant of Oct-1 represses NF-B-dependent reporter gene expression. Biochemically, Oct-1 interacts with p65, suggesting that Oct-1 is involved in the regulation of NF-B transactivation function. NF-B-dependent gene expression is more pronounced in Oct-1-deficient than in wild-type murine embryonic fibroblasts, and reintroduction of human Oct-1 abolishes these differences. Finally, the cytokine interleukin-6 induces Oct-1 gene expression, providing a biologically relevant means by which NF-B-dependent gene expression can be selectively reverted by Oct-1 to quiescent levels.

Received for publication, July 20, 2006 , and in revised form, December 14, 2006.

^* These studies were supported by National Institutes of Health (NIH) Grant F31HL-74452 (to N. G. P.) and NIH Grants DK-54802 (to D. W. R.) and HL-45462 (to T. C.). 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.

¹ Present address: Dept. of Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115.

² Present address: Goldman, Sachs & Co., New York, NY 10004.

³ Present address: Wood MacKenzie, Boston, MA 02110.

⁴ These authors contributed equally to this work.

⁵ To whom correspondence should be addressed: Dept. of Pathology, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2662; Fax: 617-730-0555; E-mail: tcollins{at}rics.bwh.harvard.edu.

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