Cytokines function as extracellular stimuli that activate a cascade of intracellular pathways regulating growth, differentiation, and the immune response. Our long range goal is to understand the intracellular pathways that are activated in response to interferons (IFNs) and interleukin-2 (IL-2) and lead to the induction of specific gene expression. In addition, the ability of the adenoviral E1A oncogene to block the IFN signal transduction pathway will be investigated to gain insight into its mechanism of action in oncogenic transformation and in evasion of a primary defense response of the cell. IFNs are unique among the cytokines because they confer resistance to viral infection. In addition they inhibit the growth of normal and tumorigenic cells, and induce the differentiation and activation of a variety of immune cells. IFNs have been approved throughout the world for the treatment of a variety of viral and malignant disorders. Recent studies of signal transduction stimulated by IFNs have defined a direct pathway that initates at a cell surface receptor and culminates at target genes in the nucleus. After IFN binding, nonreceptor tyrosine kinases are activated that phosphorylate latent DNA-binding factors in the cytoplasm. The phosphorylated factors form complexes that translocate to the nucleus and bind to specific DNA sequences in the promoters of induced genes. These signal transducers and activators of transcription (STATs) have also been found in other cytokine signal pathways. We have discovered a putative STAT molecule activated by the cytokine IL-2 that may serve to mediate the physiological effects of IL-2 on the immune system that have led to its use in immunotherapy of cancer and infectious disease.
The aims of the proposed project are to use biochemical and molecular techniques to understand the mechanism of action of these STAT molecules and how the adenoviral E1A oncogene blocks transcription factor activation by IFN.
| Reich, Nancy C (2007) STAT dynamics. Cytokine Growth Factor Rev 18:511-8 |
| Liu, L; Gao, Y; Qiu, H et al. (2006) Identification of STAT3 as a specific substrate of breast tumor kinase. Oncogene 25:4904-12 |
| Liu, Ling; McBride, Kevin M; Reich, Nancy C (2005) STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci U S A 102:8150-5 |
| Gilbert, M Melissa; Weaver, Brian K; Gergen, J Peter et al. (2005) A novel functional activator of the Drosophila JAK/STAT pathway, unpaired2, is revealed by an in vivo reporter of pathway activation. Mech Dev 122:939-48 |
| Banninger, Gregg; Reich, Nancy C (2004) STAT2 nuclear trafficking. J Biol Chem 279:39199-206 |
| McDonald, Christine; Vanscoy, Sarah; Hearing, Patrick et al. (2004) Induction of genes involved in cell cycle progression by interleukin-4. J Interferon Cytokine Res 24:729-38 |
| Gomez, Dolores; Reich, Nancy C (2003) Stimulation of primary human endothelial cell proliferation by IFN. J Immunol 170:5373-81 |
| McBride, Kevin M; Reich, Nancy C (2003) The ins and outs of STAT1 nuclear transport. Sci STKE 2003:RE13 |
| Reich, Nancy C (2002) Nuclear/cytoplasmic localization of IRFs in response to viral infection or interferon stimulation. J Interferon Cytokine Res 22:103-9 |
| McBride, Kevin M; Banninger, Gregg; McDonald, Christine et al. (2002) Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-alpha. EMBO J 21:1754-63 |
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