Interferon-dependent transcriptional activation: signal transduction without second messenger involvement?
Two specific macromolecular interactions are known to underlie the demonstrated transcriptional stimulation of different sets of genes incident to the binding of different polypeptide ligands to cells. The initial polypeptide-receptor interaction is widely recognized to be specific. It is also well established that the binding of specific transcription factors to well-defined DNA sites activates specific genes. In this paper, we suggest that a third, equally specific protein-protein interaction links the first two specific interactions and ensures the high specificity required in these pathways. We propose that a receptor-recognition protein is required to recognize the bound receptor. This receptor-recognition protein might itself be part of a transcription factor or might interact directly with a transcription factor that would thereby be activated and translocated to the nucleus to participate in gene activation. According to this hypothesis, no global changes in second messenger concentrations are necessary, and the enzymatic properties of the receptor-recognition protein(s) need not be specified. Phosphorylations of, or by, receptor-bound proteins would not, of course, be excluded. But such modifications during ligand-mediated signal transduction would not depend on global second messenger changes. This model is derived from studies of the proteins involved in interferon (IFN)-stimulated gene transcription. It is now established that interferon-alpha (IFN alpha) activates a multisubunit transcription factor in the cell cytoplasm, and that this factor then moves to the nucleus to activate a set of IFN-stimulated genes.(ABSTRACT TRUNCATED AT 250 WORDS)
Levy
D
D
Department of Pathology, New York University School of Medicine, 10016.
Darnell
J E
JE
D004268:DNA-Binding Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007372:Interferons / Q000494:pharmacology*; D008024:Ligands; D008954:Models, Biological; D010703:Phorbol Esters / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D013268:Stimulation, Chemical; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008024:Ligands; D010703:Phorbol Esters; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D007372:Interferons; D019204:GTP-Binding Proteins