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Transcriptional Inhibition of Ha-ras in Interferon-induced Revertants of ras-transformed Mouse Cells¹

Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799

Elevation in Ha-ras expression, due to transcriptional activation or gene amplification, is associated with oncogenic transformation of NIH 3T3 cells. We have previously shown that murine interferon (IFN)-/ß induced phenotypic reversion of NIH 3T3 cells transformed by long terminal repeat (LTR)-activated c-Ha-ras. The revertants produced decreased amounts of ras-encoded M_r 21,000 protein. We have now determined the molecular level at which LTR-ras regulation occurred. Nuclear run-on experiments revealed a selective inhibition of ras transcription in IFN-treated revertants. There was no apparent additional posttranscriptional control by IFN as judged by the unchanged half-life of ras transcripts. Inhibition of ras RNA synthesis was seen only in conjunction with long-term IFN treatment and was limited to the revertants, a population of cells that maintained sensitivity to IFN during the prolonged exposure. The reduction in ras activity appeared responsible in part for the loss of tumorigenicity in treated cells and was stable for several weeks after treatment had been discontinued.

¹ This research was supported by NIH Grant RO ICA 39039, by a National Foundation for Cancer Research Agreement and by a grant from the Elsa U. Pardee Foundation.

² To whom requests for reprints should be addressed.

Received 2/23/88. Revised 5/24/88. Accepted 6/16/88.