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We found that much of the immediate response to IFNs is mediated by transcriptional activation of a discrete set of IFN-stimulated genes through the action of a novel transcription factor that binds an IFN-sensitive enhancer element only following IFN treatment. Purifying and cloning this transcription factor showed that it consists of several different polypeptides that are regulated by tyrosine phosphorylation, causing this multimeric factor to assemble and to translocate to the nucleus. We study the mechanisms of subunit assembly, the kinases responsible for regulated tyrosine phosphorylation, and signal coupling between IFN receptors and the kinase/transcription factor complex.
Additionally, we are investigating the normal physiological relevance of these signaling pathways in vivo with gene targeting. We disrupted the genes for individual signaling proteins in embryonic stem cells through homologous recombination. We used these altered stem cells to populate normal mouse blastocysts to produce laboratory mice strains carrying the specific mutations. Now we are studying the phenotypes of the mutant mice to determine the role for cytokine signaling pathways in development, immune responses, and defense against pathogens. This has enabled us to establish several disease models that can now be studied at the molecular level.
One of the signaling proteins we study is Stat3, a transcription factor responsible for gene expression in response to many cytokines, especially those of the IL6 family. We have disrupted the gene for Stat3 in mice, but because this disruption led to an embryonic lethal phenotype, we have also constructed a conditional mutant version of Stat3 by using the Cre-loxP system. We can cause the Stat3 disruption inducibly in specific tissues or cell types and therefore study the phenotype resulting from loss of Stat3 function, for instance in B lymphocytes or liver. These studies will help define the molecular basis of B cell proliferation and maturation and of the acute phase response to pathogens. In combination with genetic models of IFN deficiency, we are examining aspects of the innate immune response.
One of the components of the innate immune response is the ability to respond to virus infection by production of IFN. We have defined an essential transcription factor for induction of members of the IFN-alpha gene family. This protein, IRF7, becomes phosphorylated specifically in virus-infected cells, causing it to translocate to the nucleus, bind DNA, and activate transcription. We have defined the structure/function relationships for its different activities and are pursuing the role for this protein in responses to a variety of infectious agents. Knowledge from these projects is being used to develop novel antiviral agents.
STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation
Gough, Daniel J; Marie, Isabelle J; Lobry, Camille; Aifantis, Iannis; Levy, David E
2014-10-13; 0006-4971,Blood - id: 1298802, year: 2014 Journal Article
The human RVB complex is required for efficient transcription of type I interferon-stimulated genes
Gnatovskiy, Leonid; Mita, Paolo; Levy, David E
2013-10-24; 0270-7306,Molecular & cellular biology - id: 575612, year: 2013 Journal Article; Research Support, N.I.H., Extramural
Mitochondrial STAT3 supports K-Ras driven myeloid leukaemia in vivo
Gough, Daniel J.; Levy, David E.
2013-10-09; 1043-4666,Cytokine - id: 557542, year: 2013
The MEK-ERK Pathway Is Necessary for Serine Phosphorylation of Mitochondrial STAT3 and Ras-Mediated Transformation
Gough, Daniel J; Koetz, Lisa; Levy, David E
2013-12-16; 1932-6203,PLoS one - id: 681112, year: 2013 Journal Article
STAT1-deficient mice spontaneously develop estrogen receptor alpha-positive luminal mammary carcinomas
Chan, Szeman Ruby; Vermi, William; Luo, Jingqin; Lucini, Laura; Rickert, Charles; Fowler, Amy M.; Lonardi, Silvia; Arthur, Cora; Young, Larry J. T.; Levy, David E.; Welch, Michael J.; Cardiff, Robert D.; Schreiber, Robert D.
2012-09-21; 1465-542x,Breast cancer research - id: 178169, year: 2012