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Fibroblasts Transformed by Different ras Oncogenes Show Dissimilar Patterns of Protease Gene Expression and Regulation

Department of Molecular and Cellular Biochemistry, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153

² To whom requests for reprints should be addressed, at the Department of Molecular and Cellular Biochemistry, Loyola University Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153.

NIH 3T3 cells transformed by different activated ras genes showed different patterns of protease gene expression, indicating the existence of least two pathways for NIH 3T3 transformation from mutated ras genes. In cells transformed by activated mammalian EJ-ras and chimeric EJ/vHa-ras, high constitutive levels of urokinase plasminogen activator (uPA) mRNA and/or phorbol-12-myristate-13-acetate (PMA) inducibility of the uPA mRNA was observed. However, PMA did not induce cathepsin L (CL) mRNA levels in these same cell lines. In contrast, NIH 3T3 cells transformed by homologous yeast RAS1^Leu sequences showed low levels of uPA mRNA and a lack of PMA inducibility of uPA mRNA, but did show high constitutive levels of the mRNA for CL and/or PMA inducibility of CL mRNA expression. Based on their differences in PMA inducibility these two phenotypes are designated ras^uPA+/CL- and ras^CL+/uPA-, respectively. Run-on assays indicated the differences in the levels of CL and uPA mRNA with ras transformation and phorbol ester induction are due to changes in transcription rates. Based on the observation of the two ras-transformed phenotypes for protease expressions, we asked whether uPA and CL can substitute for each other in the promotion of experimental metastasis. Injection of in vitro antisense inhibited cells in nude mice showed an inhibition of lung colonization by anti-uPA only in the ras^uPA+/CL- phenotype and by anti-CL only in the ras^CL+/uPA- phenotype. The data thus show the existence of two distinct activated ras-transformed metastatic phenotypes induced in the same parental cell line and that uPA or CL protease expressions alternatively facilitate the metastasis of cells with one ras phenotype and not with the other.

¹ Portions of this work will be submitted in partial fulfillment of the requirements for a Ph.D. degree in the Department of Molecular and Cellular Biochemistry, Loyola University of Chicago.

³ Member of the Program in Molecular Biology.

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.

Received 6/19/92. Accepted 9/24/92.

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