Hepatocyte Growth Factor Releases Epithelial and Endothelial Cells from Growth Arrest Induced by Transforming Growth Factor-1

doi:10.1074/jbc.271.8.4342

Hepatocyte Growth Factor Releases Epithelial and Endothelial Cells from Growth Arrest Induced by Transforming Growth Factor-1 (*)

From the (1)Departments of Virology, the Haartman Institute and
(2)Dermatology and Venereology, University of Helsinki, FIN-00014 Helsinki, Finland

^¶ To whom correspondence should be addressed:
Dept. of Virology, University of Helsinki, P. O. Box 21 (Haartmaninkatu 3), FIN-00014, University of Helsinki, Helsinki, Finland
. Tel.: 358-0-434-6476; Fax: 358-0-434-6491.

Abstract

Human lung fibroblasts and Mv1Lu mink lung epithelial cells were used as a model to study the role of extracellular matrix in epithelial-mesenchymal interactions. Extracellular matrices of fibroblasts were found to contain growth promoting activity that reduced the sensitivity of Mv1Lu cells to the growth inhibitory effects of transforming growth factor-β (TGF-β). The majority of the activity was identified as hepatocyte growth factor/scatter factor (HGF) by inhibition with specific antibodies and by reconstitution of the effect by recombinant HGF. HGF induced cell proliferation when contact-inhibited Mv1Lu cells were trypsinized and plated in the presence of TGF-β1. The effect was valid also in assays where Madin-Darby canine kidney epithelial cells or bovine capillary endothelial cells were used. The multiplication of chronically TGF-β1 inhibited Mv1Lu cells was also induced by HGF. In addition, HGF induced anchorage independent growth of Mv1Lu cells that was refractory to TGF-β1 growth inhibition. Immunoprecipitation analysis indicated that HGF prevented the suppression of Cdk4 and Cdk2, but not the induction of p21, by TGF-β1. Since both TGF-β1 and HGF require proteolysis for activation, the results imply that proteolytic activity of epithelial and endothelial cells directs their responses to signals from mesenchymal-type extracellular matrices, and that during development, matrix-bound growth and invasion promoting and suppressing factors are activated in a coordinated manner.

Footnotes

↵^§ Predoctoral fellow of the Academy of Finland.
↵* This work was supported by the Academy of Finland, Sigrid Juselius Foundation, Biocentrum Helsinki, Finnish Cancer Organizations, The Research and Science Foundation of Farmos, Novo Nordisk Foundation, and the University of Helsinki. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TGF-β

transforming growth factor-β

HGF

hepatocyte growth factor/scatter factor

MDCK

Madin-Darby canine kidney cells

MEM

minimal essential medium

FCS

fetal calf serum

PBS

phosphate-buffered saline

PAGE

polyacrylamide gel electrophoresis.
↵²J. Taipale and J. Keski-Oja, unpublished data.
- Received June 19, 1995.
- Revision received October 27, 1995.