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J. Biol. Chem., Vol. 278, Issue 34, 31691-31700, August 22, 2003

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The Role of Collagen Structure in Mitogen Stimulation of ERK, Cyclin D1 Expression, and G₁-S Progression in Rat Hepatocytes^*

John T. Fassett  , Diane Tobolt , Christopher J. Nelsen ¶, Jeffrey H. Albrecht ¶ and Linda K. Hansen  ||

From the Department of Laboratory Medicine and Pathology, University of Minnesota, and the ^¶Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota 55455

Adhesion to type 1 collagen can elicit different cellular responses dependent upon whether the collagen is in a fibrillar form (gel) or monomeric form (film). Hepatocytes adherent to collagen film spread extensively, express cyclin D1, and increase DNA synthesis in response to epidermal growth factor, whereas hepatocytes adherent to collagen gel have increased differentiated function, but lower DNA synthesis. The signaling mechanisms by which different forms of type I collagen modulate cell cycle progression are unknown. When ERK MAP kinase activation was analyzed in hepatocytes attached to collagen film, two peaks of ERK activity were demonstrated. Only the second peak, which correlated with an increase of cyclin D1, was required for G₁-S progression. Notably, this second peak of ERK activity was absent in cells adherent to collagen gel, but not required in the presence of exogenous cyclin D1. Expression of activated mutants of the Ras/Raf/MEK signaling pathway in cells adherent to collagen gel restored ERK phosphorylation and DNA synthesis, but differentially affected cell shape. Although Ras, Raf, and MEK all increased expression of cyclin D1 on collagen film, only Ras and Raf significantly up-regulated cyclin D1 levels on collagen gel. These results demonstrate that adhesion to polymerized collagen induces growth arrest by inhibiting the Ras/ERK-signaling pathway to cyclin D1 required in late G₁.

Received for publication, January 27, 2003 , and in revised form, May 21, 2003.

^* This work was supported in part by National Science Foundation Grant MCB-9808205 (to L. K. H.) and National Institutes of Health Grants 2R01-DK45371 (to L. K. H.) and DK54921 (to J. H. A.). 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 Training Grant CA09138.

^|| To whom correspondence should be addressed. E-mail: hanse066{at}tc.umn.edu.

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