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Molecular and Cellular Biology, May 1999, p. 3654-3663, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Hepatocyte Growth Factor Releases Mink Epithelial Cells from Transforming Growth Factor beta 1-Induced Growth Arrest by Restoring Cdk6 Expression and Cyclin E-Associated Cdk2 Activity

Minna Tsubari, Jussi Taipale, Erja Tiihonen, Jorma Keski-Oja, and Marikki Laiho*

Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland

Received 22 May 1998/Returned for modification 14 July 1998/Accepted 22 February 1999

Transforming growth factor beta  (TGF-beta ) potently suppresses Mv1Lu mink epithelial cell growth, whereas hepatocyte growth factor (HGF) counteracts TGF-beta -mediated growth inhibition and induces Mv1Lu cell proliferation (J. Taipale and J. Keski-Oja, J. Biol. Chem. 271:4342-4348, 1996). By addressing the cell cycle regulatory mechanisms involved in HGF-mediated release of Mv1Lu cells from TGF-beta inhibition, we show that increased DNA replication is accompanied by phosphorylation of the retinoblastoma protein and alternative regulation of cyclin-Cdk-inhibitor complexes. While TGF-beta treatment decreased the expression of Cdk6, this effect was counteracted by HGF, followed by partial restoration of cyclin D2-associated kinase activity. Notably, HGF failed to prevent TGF-beta induction of p15 and its association with Cdk6. However, HGF reversed the TGF-beta -mediated decrease in Cdk6-associated p27 and cyclin D2-associated Cdk6, suggesting that HGF modifies the TGF-beta response at the level of G1 cyclin complex formation. Counteraction of TGF-beta regulation of Cdk6 by HGF may in turn affect the association of p27 with Cdk2-cyclin E complexes. Though HGF did not differentially regulate the total levels of p27 in TGF-beta -treated cells, p27 immunodepletion experiments suggested that upon treatment with both growth factors, less p27 is associated with Cdk2-cyclin E complexes, in parallel with restoration of the active form of Cdk2 and the associated kinase activity. The results demonstrate that HGF intercepts TGF-beta cell cycle regulation at multiple points, affecting both G1 and G1-S cyclin kinase activities.

* Corresponding author. Mailing address: Haartman Institute, Department of Virology, University of Helsinki, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland. Phone: 358-9-1912-6509. Fax: 358-9-1912-6491. E-mail: Marikki.Laiho{at}Helsinki.FI.

Molecular and Cellular Biology, May 1999, p. 3654-3663, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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