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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.
Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation
Daniels, Garrett; Zhang, Xinmin; Zhong, Xuelin; Santiago, Larion; Wang, Ling Hang; Wu, Xinyu; Zhang, Jack Y; Liang, Fengxia; Li, Xin; Neubert, Thomas A; Steinke, Laurey; Shen, Ying; Basch, Ross; Schneider, Robert; Levy, David E; Lee, Peng. Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation. Oncotarget. 2016 Jun 28;7(26):39556-39571 (2092672)
PKR Transduces MDA5-Dependent Signals for Type I IFN Induction
Pham, Alissa M; Santa Maria, Felicia Gilfoy; Lahiri, Tanaya; Friedman, Eugene; Marie, Isabelle J; Levy, David E. PKR Transduces MDA5-Dependent Signals for Type I IFN Induction. PLoS pathogens. 2016 Mar 3;12(3):e1005489-e1005489 e1005489 (2009422)
Insertional Mutagenesis Identifies a STAT3/Arid1b/beta-catenin Pathway Driving Neurofibroma Initiation
Wu, Jianqiang; Keng, Vincent; Patmore, Deanna M; Kendall, Jed J; Patel, Ami V; Jousma, Edwin; Jessen, Walter J; Choi, Kwangmin; Tschida, Barbara R; Silverstein, Kevin A T; Fan, Danhua; Schwartz, Eric B; Fuchs, James R; Zou, Yuanshu; Kim, Mi-Ok; Dombi, Eva; Levy, David E; Huang, Gang; Cancelas, Jose A; Stemmer-Rachamimov, Anat O; Spinner, Robert J; Largaespada, David A; Ratner, Nancy. Insertional Mutagenesis Identifies a STAT3/Arid1b/beta-catenin Pathway Driving Neurofibroma Initiation. Cell reports. 2016 Feb 18;14(8):1979-1990 (1965402)
A synthetic lethal interaction between glutathione synthesis and mitochondrial reactive oxygen species provides a tumor specific vulnerability dependent on STAT3
Garama, Daniel J; Harris, Tiffany J; White, Christine L; Rossello, Fernando J; Abdul-Hay, Maher; Gough, Daniel J; Levy, David E. A synthetic lethal interaction between glutathione synthesis and mitochondrial reactive oxygen species provides a tumor specific vulnerability dependent on STAT3. Molecular & cellular biology. 2015 Aug 17;35(21):3646-3656 (1732222)
STAT3 regulated ARF expression suppresses prostate cancer metastasis
Pencik, Jan; Schlederer, Michaela; Gruber, Wolfgang; Unger, Christine; Walker, Steven M; Chalaris, Athena; Marie, Isabelle J; Hassler, Melanie R; Javaheri, Tahereh; Aksoy, Osman; Blayney, Jaine K; Prutsch, Nicole; Skucha, Anna; Herac, Merima; Kramer, Oliver H; Mazal, Peter; Grebien, Florian; Egger, Gerda; Poli, Valeria; Mikulits, Wolfgang; Eferl, Robert; Esterbauer, Harald; Kennedy, Richard; Fend, Falko; Scharpf, Marcus; Braun, Martin; Perner, Sven; Levy, David E; Malcolm, Tim; Turner, Suzanne D; Haitel, Andrea; Susani, Martin; Moazzami, Ali; Rose-John, Stefan; Aberger, Fritz; Merkel, Olaf; Moriggl, Richard; Culig, Zoran; Dolznig, Helmut; Kenner, Lukas. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nature communications. 2015 Jul 22;6:7736-7736 (1683922)