Transcriptional induction of two genes in human cells by beta interferon.

Abstract

The binding of interferons to distinct cell surface receptors leads to the induction of synthesis of several unique polypeptides and their corresponding mRNAs (1)(2)(3)(4)(5)(6) (8,9). One of these cDNA clones is complementary to the mRNA for a 56-kDa protein (8), and the other, to the mRNA for 2',5'-oligo(A) synthetase (9), both of which are prominent IFN-induced protein products (7). Whether this increase in specific mRNA is based on increased transcription and/or increased stabilization of the mRNA in the cytoplasm has not been determined.In fact, whether transcriptional increases underlie the numerous biologic effects mediated by the binding of peptide hormones, growth factors, and lectins to their specific plasma membrane receptors is at present largely unknown. It is also unclear whether a polypeptide can effect an increase in specific mRNA concentration, particularly by transcriptional control, without entering the cell. Molecules such as cyclic AMP or Ca2+ or analogous "second messengers" could mediate the transcriptional stimulation of specific genes after an initial hormone-receptor interaction. Likewise, the effect of intracellular tyrosine kinase activities of membrane receptor proteins is under intense investigation, but no specific transcriptional activations have been documented as a result of these enzyme activities.A few cases have been analyzed that support the hypothesis of second messengers as transcriptional activators. Thyrotropin-releasing hormone (TRH) and epidermal growth factor (EGF) increase transcription of the prolactin gene in a pituitary cell line (10, 11). The effects of TRH can be mimicked by cyclic AMP treatment of the pituitary tumor cells. EFG-induced prolactin mRNA accumulation requires extracellular Ca2 , which implies that increased free intracellular

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…The motivation for these studies derives from evidence that IFNa and IFNg induced rapid but largely distinct changes in gene expression in target cells (Fan et al, 1988(Fan et al, , 1989Friedman et al, 1984;Larner et al, 1984;Revel and Chebath, 1986), re¯ecting their largely distinct biology of inducing direct antiviral action versus modulation of immune cell function, respectively. The discovery of a family of transcription factors that could be activated by a cell surface receptor and deliver information directly to the nucleus to modulate gene expression with the same speci®city inherent in the ligand-receptor interaction, provided an appealing explanation of how speci®city is maintained during signal transduction (Levy and Darnell, 1990).…”

Properties of Natural and Hybrid Murine Alpha Interferons

“…To elicit their biological properties it is necessary that the IFNs bind to specific surface receptors on the target cells. Subsequently, the expression of several genes within the target cells is affected (Fellous et al, 1982;Friedman et al, 1984;Larner et al, 1984;Shulman & Revel, 1980). So far, however, little is known about the precise relationship between the different biological and molecular changes induced by IFNs.…”

Differential regulation of interferon‐induced mRNAs and c‐myc mRNA by α‐ and γ‐interferons

“…. When an IFN binds to its receptor there is an increase in both the rates of transcription and the steady-state levels of induced mRNAs [15, 17, 181. In contrast the levels of at least one mRNA, c-myc, is reduced in cells treated with p-IFN [19].…”

“…When the effects of a-and y-interferons were compared, the induced levels and kinetics were very similar for one mRNA (1-8) but were significantly different for the others. One mRNA (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) was induced more than 100-fold by a-interferon but not significantly by y-interferon. Parallel analysis of the level of c-myc mRNA showed it to decrease twofold in response to a-interferon, but to increase more than threefold in response to y-interferon, despite a more profound inhibition of cell growth by the latter.…”