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Regulation of Smooth Muscle -Actin Promoter in ras-transformed Cells: Usefulness for Setting Up Reporter Gene-based Assay System for Drug Screening

Department of Tumor Biology, Schering-Plough Research Institute, Bloomfield, New Jersey 07003

¹ To whom requests for reprints should be addressed.

Oncogenic activation of ras results in changes in the transcription of several genes leading to uncontrolled cell growth. In this paper, we demonstrate that transformation of fibroblast cells by the ras oncogene leads to transcriptional repression of the smooth muscle -actin promoter. Transient transfection analysis of plasmids containing the 5' upstream region of the human -actin gene fused to human growth hormone or bacterial chloramphenicol acetyltransferase coding sequences into Rat-2 and ras-transformed Rat-2 (HO6) cells indicates that -actin promoter is repressed in ras-transformed cells. In addition, stable rat fibroblast cell lines expressing human growth hormone or β-galactosidase under the control of -actin promoter exhibit repressed reporter gene activity following transformation by the ras oncogene. -Actin promoter-driven β-galactosidase activity is derepressed in revertants of ras-transformed stable cell lines. This revertant cell line expresses elevated levels of ras p21 protein and is resistant to retransformation by Ki and Ha-ras oncogenes. The revertant may have either a defective target protein whose activity is essential for the transforming activity of ras or an activated tumor suppressor gene which can suppress the activity of ras. These results indicate that smooth muscle -actin promoter activity is a sensitive marker to follow phenotypic changes following transformation by ras and subsequent reversion. The advantages of this -actin promoter-reporter gene assay system to screen for drugs that inhibit the transforming activity of ras, either directly or indirectly, are discussed.

² Present address: DNAX Research Institute, Palo Alto, CA 94304.

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 9/30/92.

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