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J. Biol. Chem., Vol. 279, Issue 33, 34530-34536, August 13, 2004

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Epidermal Growth Factor Receptor Transactivation Mediates Tumor Necrosis Factor-induced Hepatocyte Replication^*

Gretchen M. Argast, Jean S. Campbell¶, John T. Brooling¶, and Nelson Fausto¶||

From the Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309 and ^¶Department of Pathology, University of Washington, Seattle, Washington 98195

Tumor necrosis factor (TNF) has multiple biological effects such as participating in inflammation, apoptosis, and cell proliferation, but the mechanisms of its effects on epithelial cell proliferation have not been examined in detail. At the early stages of liver regeneration, TNF functions as a priming agent for hepatocyte replication and increases the sensitivity of hepatocytes to growth factors such as transforming growth factor (TGF); however, the mechanisms by which TNF interacts with growth factors and enhances hepatocyte replication are not known. Using the AML-12 hepatocyte cell line, we show that TNF stimulates proliferation of these cells through transactivation of the epidermal growth factor receptor (EGFR). The transactivation mechanism involves the release of TGF into the medium through activation of the metalloproteinase TNF-converting enzyme (also known as ADAM 17). Binding of the ligand to EGFR initiates a mitogenic cascade through extracellular signal-regulated kinases 1 and 2 and the partial involvement of protein kinase B. TNF-induced release of TGF and activation of EGFR signaling were inhibited by TNF protease inhibitor-1, an agent that interferes with TNF-converting enzyme activity. We suggest that TNF-induced transactivation of EGFR may provide an early signal for the entry of hepatocytes into the cell cycle and may integrate proliferative and survival pathways at the start of liver regeneration.

Received for publication, May 21, 2004 , and in revised form, June 14, 2004.

^* This work was supported in part by National Institutes of Health Grant CA-23226. 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.

Supported by National Institutes of Health Grant T32-ES07032-23.

^|| To whom correspondence should be addressed: Dept. of Pathology, University of Washington, Box 357470, Seattle, WA 98195. Tel.: 206-616-4550; Fax: 206-616-1943; E-mail: nfausto{at}u.washington.edu.

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