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J. Biol. Chem., Vol. 281, Issue 24, 16428-16435, June 16, 2006

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Coordinate Inhibition of Cytokine-mediated Induction of Ferritin H, Manganese Superoxide Dismutase, and Interleukin-6 by the Adenovirus E1A Oncogene^*

Jamie E. Jennings-Gee, Yoshiaki Tsuji^¶1, E. Christine Pietsch², Elizabeth Moran^||, J. S. Mymryk^**, Frank M. Torti^¶, and Suzy V. Torti^¶3

From the Departments of Biochemistry, Cancer Biology, and the ^¶Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, the ^||Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and the ^**London Regional Cancer Program, Room A4-827, Cancer Research Laboratory Program, London, Ontario N6A 4L6, Canada

Adenovirus E1A sensitizes cells to the cytotoxic action of tumor necrosis factor (TNF-). This effect has been attributed to direct blockade of NF-B activation, as well as to increased activation of components of the apoptotic pathway and decreases in inhibitors of apoptosis. In this report we evaluated the mechanism by which E1A modulates the expression of the cytokine-inducible cytoprotective genes manganese superoxide dismutase (MnSOD), interleukin-6 (IL-6), and ferritin heavy chain (FH). We observed that E1A blocks induction of MnSOD, IL-6, and FH by TNF- or IL-1. Because NF-B plays a role in cytokine-dependent induction of MnSOD, IL-6, and FH, we assessed the effect of E1A on NF-B in cells treated with TNF. IB, the inhibitor of NF-B, was degraded similarly in the presence and absence of E1A. TNF induced a quantitatively and temporally equivalent activation of NF-B in control and E1A-transfected cells. However, TNF-dependent acetylation of NF-B was diminished in cells expressing E1A. E1A mutants unable to bind p400 or the Rb family proteins were still capable of repressing TNF-dependent induction of FH. However, mutants of E1A that abrogated binding of p300/CBP blocked the ability of E1A to repress TNF-dependent induction of FH. These results suggest that p300/CBP is a critical control point in NF-B-dependent transcriptional regulation of cytoprotective genes by cytokines.

Received for publication, January 3, 2006 , and in revised form, April 11, 2006.

^* This work was supported in part by National Institutes of Health Grant R37 DK42412 (to F. M. T.). 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 Environmental and Molecular Toxicology, North Carolina State University, Campus Box 7633, Raleigh, NC 27695.

² Present address: Cell and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.

³ To whom correspondence should be addressed: Dept. of Biochemistry, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157. Tel.: 336-716-9357; Fax: 336-716-0255; E-mail: storti{at}wfubmc.edu.

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