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A Link between ras and Metastatic Behavior of Tumor Cells: ras Induces CD44 Promoter Activity and Leads to Low-Level Expression of Metastasis-specific Variants of CD44 in CREF Cells¹

Kernforschungszentrum Karlsruhe, Institut für Genetik und Toxikologie, P. O. Box 3640, D-7500 Karlsruhe 1, Germany [M. H., W. R., U. G., V. Z. P. H., H. P.]; Department of Microbiology and Immunology, University of Kentucky, Medical Center, Lexington, Kentucky 40536-0084 [S. G. Z.]; and Instituts für Radiologie und Pathophysiologie [M. Z.] and Immunologie, [R. B. L.], Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 280, D-6900 Heidelberg 1, Germany

The activated oncogene c-Ha-ras induces expression of the surface glycoprotein CD44 in cloned rat embryonic fibroblasts (CREF). Induction is transcriptional as shown by transient cotransfections of c-Ha-ras expression constructs and CD44 promoter reporter gene constructs and depends on the presence of an AP-1 binding site at position –110. Increased transcript levels for the standard isoform of CD44 (CD44s) are accompanied by the appearance of alternatively spliced RNAs and the synthesis of variants of CD44 (CD44v). These CD44v molecules differ from the standard type by the addition of sequences in the extracellular portion of the molecules. The occurrence of CD44v molecules in CREF cells upon induction of the CD44 promoter is probably due to leakiness of the splice control in these cells since stable transfection with c-Ha-ras does not alter the CD44v/total CD44 ratio. Upon ras overexpression, however, using an inducible mouse mammary tumor virus-ras construct, a transient increase of CD44v/total CD44 ratio of 3–4 has been determined suggesting that a burst of ras expression, in the genetic background of CREF cells, influences both promoter activity and splice control or accuracy. The expression of CD44v proteins is responsible for the metastatic potential in a variety of tumors (U. Günthert et al., Cell, 65: 13–24, 1991). Also in CREF cells expression of CD44v correlates with metastatic behavior. ras-transfected CREF cells are not only fully transformed but also give rise to metastatic spread as measured in the spontaneous metastasis assay. The adenoviral oncogene EIA counteracts ras-induced promoter function and, consequently, inhibits metastatic behavior without extinguishing transformation.

¹ This work was supported by Grant He551/7-1 from the Deutsche Forschungsgemeinschaft.

² Present address: Forschungsinstitut für Molekulare Pathologie (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.

³ Present address: Basel Institute for Immunology, Grenzacher Str. 487, CH-4058 Basel, Switzerland.

⁴ Present address: Schering AG, Postfach 650311, D-1000 Berlin 65, Germany.

Received 9/ 9/92. Accepted 1/23/93.

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