Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multifunctional signal transducer and activator of transcription (STAT) proteins relay signals from the cell membrane to the nucleus in response to cytokines and growth factors. STAT4 becomes activated when cells are treated with interleukin-12, a key cytokine regulator of cell-mediated immunity. Upon activation, dimers of STAT4 bind cooperatively to tandem interferon-gamma activation sequences (GAS elements) near the interferon-gamma gene and stimulate its transcription. The amino-terminal domain of STAT4 (STAT4(1-124)) is required for cooperative binding interactions between STAT4 dimers and activation of interferon-gamma transcription in response to interleukin-12. We have overproduced this domain of human STAT4 (hSTAT4(1-124)) in Escherichia coli and purified it to homogeneity for structural studies. The circular dichroism spectrum of hSTAT4(1-124) indicates that it has a well ordered conformation in solution. The translational diffusion constant of hSTAT4(1-124) was determined by nuclear magnetic resonance methods and found to be consistent with that of a dimer. The rotational correlation time (tauc) of hSTAT4(1-124) was estimated from 15N relaxation to be 16 ns; this value is consistent with a 29-kDa dimeric protein. These results, together with the number of signals observed in the two-dimensional 1H-15N heteronuclear single quantum coherence spectrum of uniformly 15N-labeled protein, indicate that hSTAT4(1-124) forms a stable, symmetric homodimer in solution. Cooperativity in native STAT4 probably results from a similar or identical interaction between the amino-terminal domains of adjacent dimers bound to DNA.
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PMID:The amino-terminal domain of human STAT4. Overproduction, purification, and biophysical characterization. 964 77

Cytokines, IL-2, IL-4, IL-6, IL-7, IL-12, and IL-15 are key regulators of human peripheral blood T and NK cell activation and differentiation but the precise mechanisms that give rise to their differential activities within these cells are not clear. Recent studies reveal that a family of transcription factors, signal transducers and activators of transcription (STATs) directly mediate many cytokine signals. We analyzed the activation of STATs in primary human T and NK cells by a variety of specific cytokines. We demonstrate that IL-12 induces STAT4 only in freshly isolated primary NK cells, but not in primary T cells, consistent with the lack of the IL-12 receptor in resting T cells. In contrast, IL-4 induces different C epsilon GAS DNA-protein binding complexes in both T and NK cells. Moreover, IL-4 costimulation with IL-2 or IL-12 does not alter their own preferential GAS-like DNA binding patterns when C epsilon-, Fc gamma RI-, and SIE GAS motif containing oligonucleotide probes are compared, suggesting that induction of GAS-like DNA-protein binding complexes by IL-2, IL-4, and IL-12 is highly selective and represents one important factor in determining specific gene activation. In addition, IL-6 and IL-2 synergistically induce homo- and heterodimerized STAT1 alpha and STAT3 in both NK and T cells, consistent with their reported synergism in modulating perforin gene expression. We further demonstrated that IL-2, -7, and -15 induce multiple STAT proteins, including STAT5a, STAT5b, STAT1 alpha, STAT3, and another unidentified Fc gamma RI GAS DNA-binding protein. Finally, we observed that activated STAT5a and STAT5b proteins form distinct Fc gamma RI GAS binding patterns in T and NK cells, suggesting that they might have different roles in gene regulation. Our data provide evidence that the differential responses in gene expression and cell activation seen in primary NK and T cells on direct stimulation with different cytokines may be a direct result of distinct activation of STAT transcription factors.
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PMID:Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells. 971 65

Interferon-alpha (IFN-alpha) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evidence that IFN-alpha has an important role in T-cell biology. We have analyzed the expression of IL-2Ralpha, c-myc, and pim-1 genes in anti-CD3-activated human T lymphocytes. The induction of these genes is associated with interleukin-2 (IL-2)-induced T-cell proliferation. Treatment of T lymphocytes with IFN-alpha, IL-2, IL-12, and IL-15 upregulated IL-2Ralpha, c-myc, and pim-1 gene expression. IFN-alpha also sensitized T cells to IL-2-induced proliferation, further suggesting that IFN-alpha may be involved in the regulation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2Ralpha, pim-1, and IRF-1 GAS elements after cytokine stimulation, we observed IFN-alpha-induced binding of STAT1, STAT3, and STAT4, but not STAT5 to all of these elements. Yet, IFN-alpha was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN-alpha enhanced tyrosine phosphorylation of STAT1, STAT3, STAT4, STAT5a, and STAT5b. IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS elements. Taken together, our results suggest that IFN-alpha, IL-2, IL-12, and IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN-alpha as a T-cell regulatory cytokine.
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PMID:Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. 1006 71