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)

Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80-77kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94kDa) and B (94-92kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.
 ...
PMID:Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages. 1592 92

Intercellular adhesion molecule-1 (ICAM-1), an inducible cell adhesion glycoprotein of the immunoglobulin supergene family and cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, are overexpressed by proinflammatory mediators in a wide variety of cell types. These stimuli increase ICAM-1 or COX-2 expression primarily through activation of ICAM-1 or COX-2 gene transcription. The architecture of the ICAM-1 or COX-2 promoter is complex, containing a large number of binding site for inducible transcription factors, the most important of which is NF-kB. NF-kB acts in concert with other transcription factors or transcriptional coactivators which facilitate the assembly of distinct stereospecific transcription complexes on the ICAM-1 or COX-2 promoter. These transcription complexes presumably mediate the induction of ICAM-1 or COX-2 expression in different cell types and in response to different stimuli. In this review, I summarize the current understanding of ICAM-1 and COX-2 gene regulation with a particular emphasis on the transcription factors or coactivators, and signal transduction pathways critical for their expression. A PKC-dependent c-Src pathway activating NF-kB or GAS to enhance ICAM-1 or COX-2 gene expression is discussed. Furthermore, natural products and novel agents targeting on the transcription factor with potential anti-inflammation and anti-tumor activity are also discussed.
 ...
PMID:Signal transduction pathways of inflammatory gene expressions and therapeutic implications. 1701 43