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J. Biol. Chem., Vol. 279, Issue 9, 7438-7446, February 27, 2004

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Tumor Necrosis Factor Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis^*

Wen Hong Shen, Yuxin Yin, Suzanne R. Broussard, Robert H. McCusker, Gregory G. Freund¶, Robert Dantzer||, and Keith W. Kelley**

From the Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, the Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, the ^¶Department of Pathology, College of Medicine, University of Illinois, Urbana, Illinois 61801, and ^||Integrative Neurobiology, FRE CNRS, UMR INRA-Bordeaux 2, Institut François Magendie des Neurosciences, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France

Cyclin A is required for cell cycle S phase entry, and its overexpression contributes to tumorigenesis. Release of pre-existing E2Fs from inactive complexes of E2F and hypophosphorylated retinoblastoma (RB) is the prevailing dogma for E2F transcriptional activation of target genes such as cyclin A. Here we explored the hypothesis that new synthesis of E2F-1 is required for insulin-like growth factor-I (IGF-I) to induce cyclin A accumulation and RB hyperphosphorylation, events that are targeted by tumor necrosis factor (TNF) to arrest cell cycle progression. We first established that IGF-I increases expression of cyclin A, causes hyperphosphorylation of RB, and augments the mass of E2F-1 in a time-dependent manner. As expected, E2F-1 small interfering RNA blocks the ability of IGF-I to increase synthesis of E2F-1. Most important, this E2F-1 small interfering RNA also blocks the ability of IGF-I to increase cyclin A accumulation and to hyperphosphorylate RB. We next established that TNF dose-dependently inhibits IGF-I-induced phosphorylation of both RB and histone H1 by cyclin A-dependent cyclin-dependent kinases. Cyclin-dependent kinase 2 (Cdk2) mediates this suppression because co-immunoprecipitation experiments revealed that TNF reduces the amount of IGF-I-induced cyclin A that binds Cdk2, leading to a reduction in Cdk2 enzymatic activity. TNF antagonizes the ability of IGF-I to increase mass of both E2F-1 and cyclin A but not cyclin E or D1. The cytostatic property of TNF is also shown by its ability to block IGF-I-stimulated luciferase activity of a cyclin A promoter reporter. Deletion of an E2F recognition site from this reporter eliminates the regulatory effects of both IGF-I and TNF on cyclin A transcription, indicating the essential role of E2F-1 in mediating their cross-talk. Collectively, these results establish that TNF targets IGF-I-induced E2F-1 synthesis, leading to inhibition of the subsequent accumulation in cyclin A, formation of cyclin A-Cdk2 complexes, hyperphosphorylation of RB, and cell cycle arrest.

Received for publication, September 16, 2003 , and in revised form, December 16, 2003.

^* This work was supported by National Institutes of Health Grant AI50442 (to K. W. K.). 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.

^** To whom correspondence should be addressed: University of Illinois, Laboratory of Immunophysiology, Dept. of Animal Sciences, 207 Edward R. Madigan Laboratory, 1201 West Gregory Dr., Urbana, IL 61801. Tel.: 217-333-5141; Fax: 217-244-5617; E-mail: kwkelley{at}uiuc.edu.

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