BALB/c-3T3 fibroblasts resistant to growth inhibition by beta interferon exhibit aberrant platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor signal transduction.

Abstract

Several lines of evidence now exist to suggest an interaction between the platelet-derived growth factor (PDGF) growth-stimulatory signal transduction pathway and the beta interferon (IFN-j8) growth-inhibitory signal transduction pathway. The most direct examples are inhibition of PDGF-mediated gene induction and mitogenesis by IFN-4 and the effects of activators and inhibitors of the IFN-inducible double-stranded RNAdependent eIF2 kinase on expression of PDGF-inducible genes. To further investigate the nature of this PDGF/ IFN-, interaction, we selected BALB/c-3T3 cells for resistance to growth inhibition by IFN-, and analyzed the phenotypes of resulting clonal lines (called IRB cells) with respect to PDGF signal transduction. Although selected only for IFN resistance, the IRB cells were found to be defective for induction of growth-related genes c-fos, c-myc, and JE in response to PDGF. This block to signal transduction was not due to loss or inactivation of PDGF receptors, as immunoprecipitation of PDGF receptors with antiphosphotyrosine antibodies showed them to be present at equal levels in the BALB/c-3T3 and IRB cells and to be autophosphorylated normally in response to PDGF. Furthermore, treatment with other peptide growth factors (PDGF-AA, fibroblast growth factor, and epidermal growth factor) also failed to induce c-fos, c-myc, or JE expression in IRB cells. All of these growth factors, however, were able to induce another early growth-related gene, Egr-1. The block to signaling was not due to a defect in inositol phosphate metabolism, as PDGF treatment induced normal calcium mobilization and phosphotidylinositol-3-kinase activation in these cells. Activation of protein kinase C by phorbol esters did induce c-fos, c-myc, and JE in IRB cells, indicating that signaling pathways distal to this enzyme remained intact. We have previously shown that IFN-inducible enzyme activities, including doublestranded RNA-dependent eIF2 kinase and 2',5'-oligoadenylate synthetase, are normal in IRB cells. The finding that the induction of multiple growth-related genes by several independent growth factors is inhibited in these IFN-resistant cells suggests that there is a second messenger common to both growth factor and IFN signaling pathways and that this messenger is defective in these cells. Treatment of cultured cells with anti-interferon (IFN)antibodies has provided evidence that many cell types utilize the antiproliferative activity of IFN to inhibit their own proliferation via an autocrine IFN feedback mechanism (5, 6, 9, 18). The significance of this growth control mechanism is suggested by numerous reports that neutralization of the autocrine IFN or the spontaneous development of resistance to its antiproliferative effects can result in neoplasia or failure to differentiate, both of which may lead to malignancy (3, 9). Since the mechanism by which IFN inhibits cell growth is unknown, it remains to be established whether autocrine IFN has its effect by directly interacting with, and inhibiting, growth-stimulatory ...

A glycosylation-deficient endothelial cell mutant with modified responses to transforming growth factor-beta and other growth inhibitory cytokines: evidence for multiple growth inhibitory signal transduction pathways.

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Initiation Factor eIF2α Phosphorylation in Stress Responses and Apoptosis

“…The phosphorylation of eIF2a is not necessarily restricted to stressful or pathological circumstances since it is becoming apparent that it may well also be involved in the normal regulation of cell growth (Mundschau and Faller 1991;Chong et al 1992). Changes in the phosphorylation state of eIF2a, or in the activities of the relevant pro tein kinases, can occur when cell proliferation is stimulated by mitogens and growth factors (Montine and Henshaw 1989;Ito et al 1994), when mitogenic signalling is inhibited by fiavonoids such as genistein (Ito et al 1999a), or when cell differentiation is induced in several systems (Petryshyn et al 1984(Petryshyn et al , 1988Kronfeld-Kinar et al 1999).…”

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