Cell growth inhibiting activity

The antiproliferative activity of IFN type 1 has been observed on cultured cells from various tissues, e.g. fibroblasts, epithelial cells, endothelial cells, and cells of the hematopoietic system. Furthermore, normal, transformed and tumorigenic cells have been shown to be sensitive to this activity, although the degree of sensitivity varies widely. It is now clear that multiple parallel pathways are involved in IFN-mediated growth inhibition and some of the molecular targets have been identified during the past few years. In IFN-sensitive cell lines, strongly reduced DNA-bind-ing activity of the transcription factor E2F was observed and found to be associated with growth arrest in the G(1/G| phase of the cell cycle. E2F activates several genes involved in cell cycle regulation and recent reports have documented an IFN-mediated inhibition of cyclins and cyclin-dependent kinases (cdk), indicating that IFN acts, at least in part, by functional modulation of E2F. Most likely, inhibition of cdk also results in reduced phosphorylation of the retinoblastoma protein (pRB), a tumor suppressor gene known to form a complex with E2F, thus preventing its interaction with DNA target sequences. Upon phosphorylation, pRB detaches from E2F and the released factor becomes active. In addition, IFN also induces expression of pRB which predominantly exists as the underphosphorylated form able to interact with E2F. Since E2F also drives the expression of c-myc, there is also a concomitant inhibition of this cellular proto-oncogene in IFN-treated cells. The transcription factor IRFI has also been shown to cause inhibition of cell proliferation when overexpressed in cell culture. IRFI is not only involved in the regulation of IFN gene expression but is itself inducible by IFN and transactivates IFN-stimulated genes through binding to the IFN-stimulated response element (ISRE). The dsRNA-dependent kinase PKR is induced by IRFI and there is substantial evidence that PKR represents a downstream target of IRFl-mediated growth inhibition since cells engineered to overexpress a dominant negative mutant of PKR fail to respond to the antiproliferative action of IRF1.

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