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J. Biol. Chem., Vol. 279, Issue 28, 28911-28919, July 9, 2004

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Oct-1 Maintains an Intermediate, Stable State of HLA-DRA Promoter Repression in Rb-defective Cells

AN Oct-1-CONTAINING REPRESSOSOME THAT PREVENTS NF-Y BINDING TO THE HLA-DRA PROMOTER^*

Aaron R. Osborne, Hongquan Zhang¶, Gyorgy Fejer||, Kimberly M. Palubin, Melissa I. Niesen, and George Blanck**

From the Departments of Biochemistry and Molecular Biology and Pathology and Laboratory Medicine, College of Medicine, University of South Florida and the ^**Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

The cell surface HLA-DR molecule binds foreign peptide antigen and forms an intercellular complex with the T cell receptor in the course of the development of an immune response against or immune tolerance to the antigen represented by the bound peptide. The HLA-DR molecule also functions as a receptor that mediates cell signaling pathways, including as yet poorly characterized pathway(s) leading to apoptosis. Expression of HLA-DR mRNA and protein is ordinarily inducible by interferon- but is not inducible in tumor cells defective for the retinoblastoma tumor suppressor protein (Rb). In the case of the HLA-DRA gene, which encodes the HLA-DR heavy chain, previous work has indicated that this loss of inducibility is attributable to Oct-1 binding to the HLA-DRA promoter. In this report, we used Oct-1 antisense transformants to determine that Oct-1 represses the interferon- response of the endogenous HLA-DRA gene. This determination is consistent with results from a chromatin immunoprecipitation assay, indicating that Oct-1 occupies the endogenous HLA-DRA promoter when the HLA-DRA promoter is inactive in Rb-defective cells but not when the promoter is converted to a previously defined, transcriptionally competent state, induced by treatment of the Rb-defective cells with the HDAC inhibitor, trichostatin A. In vitro DNA-protein binding analyses indicated that Oct-1 prevents HLA-DRA promoter activation by mediating the formation of a complex of proteins, termed DRAN (DRA negative), that blocks NF-Y access to the promoter.

Received for publication, March 19, 2004 , and in revised form, April 19, 2004.

^* This work was supported by National Institutes of Health Grant R01 CA81497 (to G. B.). 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.

^¶ Present address: Dept. of Pathology, Harper University Hospital, Wayne State University, Detroit, MI 48201.

^|| Present address: Veterinary Medical Research Institute, Hungarian Academy of Sciences, Budapest, Hungary.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of South Florida College of Medicine, MDC Box 7, 12901 Bruce B. Downs Blvd., Tampa, FL 33612. Tel.: 813-974-9585; Fax: 813-974-7280; E-mail: gblanck{at}hsc.usf.edu.

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