Research / Clinical
Summary
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Diseases/Research Topics
Molecular Biology
Our goal is to understand the mechanisms by which interferons (IFNs) and other cytokines activate the transcription of early response genes, an event which ultimately leads to biological responses such as (anti)proliferative effects, differentiation or antiviral protection. There are three major questions in which this laboratory is interested:
1) What are the signal transduction mechanisms that permit IFNs as well as other cytokines to activate the transcription of defined cellular genes? Formation of DNA-binding complexes comprised of tyrosine phosphorylated STAT transcription factors involves the activation of members of the JAK family of tyrosine kinases. We have shown that IFNs also activate the MAP kinase pathway, which is possibly responsible for the additional serine/threonine phosphorylation of certain STAT proteins that is required for maximum transcriptional induction of IFN regulated early response genes. However, not all biological effects of the IFNs are exclusively mediated by the JAK/STAT pathway. We aim to identify alternative signal transduction mechanisms that are utilized by the IFNs to achieve their antiviral and antiproliferative effects.
2) What are the mechanisms which downregulate IFN induced gene expression and cause a desensitized state after extended exposure to the cytokine? We have found that the tyrosine phosphatase SHP-1 plays an important role as a negative regulator of the IFN activated JAK/STAT pathway. We also found evidence that a nuclear tyrosine phosphatase might be responsible for the attenuation of IFN induced transcription of early response genes by preventing the dephosphorylation of STAT proteins.
3) How can pathological events such as malignant transformation or viral infections interfere with these signal transduction pathways, therefore circumventing the antiviral and antiproliferative properties of the IFNs? Alternatively, how can disturbances in these signaling systems contribute to the development of pathological processes?
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David, M., Wong, L., Flavell, R., Thompson, S., Larner, A. and Johnson, G. (1996). STAT Activation by EGF and Amphiregulin: Requirement for the EGF Receptor Kinase, but not for Tyrosine Phosphorylation Sites or JAK1. J. Biol. Chem. 271: 915-9188.
David, M., Zhou, G., Pine, R., Dixon, J. and Larner, A. (1996). The SH2 Domain Containing Tyrosine Phosphatase PTP1D is Required for IFNa/b - induced Gene Expression. J. Biol. Chem. 271:15862-15865.
David, M., Petricoin, E., Benjamin, C., Pine, R., Weber, M. and Larner, A. (1995). Requirement for MAP Kinase (ERK2) Activity in Interferon a/b-Stimulated Gene Expression Through STAT Proteins. Science 269: 1721-1723.
David, M., Chen, H., Goelz, S., Larner, A. and Neel, B. (1995). Differential Regulation of the Interferon-a/bStimulated JAK/STAT Pathway by the SH2-Domain Containing Tyrosine Phosphatase SHPTP1. Mol. Cell. Biol.15: 7050-7058.
David, M., Grimley, P., Finbloom, D.S. and Larner, A.C. (1993). A Nuclear Tyrosine Phosphatase Downregulates Interferon Induced Gene Expression. Mol. Cell. Biol.13: 7515-7521.
David, M. and Larner, A.C.. Activation of Transcription Factors by Interferon-alpha in a Cell-Free System. (1992). Science 257: 813-815.
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