STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the α2-macroglobulin gene

Lerner, Lorena; Henriksen, Melissa A.; Zhang, Xiaokui; Darnell, James

doi:10.1101/gad.1135003

Cited by 100 publications

(89 citation statements)

References 46 publications

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“…This complex was reported to increase the transcription of ␣2-macroglobulin and fibrinogen genes via STAT3-responsive elements in their 5Ј promoter sequences. 32,33 PKC inhibitors and tyrosine kinase inhibitors universally inhibited the activity of the prototypical CTGF promoter in fibroblasts and mesangial cells 20,21 as well as DEX induction of CTGF in the tubular epithelial cells in this study. If phosphorylated STAT3 is truly involved in this signaling process, then a tyrosine kinase most likely plays a direct role because it phosphorylates STAT3.…”

Section: Discussionmentioning

confidence: 97%

Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner

Okada

Kikuta

Inoue

et al. 2006

The American Journal of Pathology

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Connective tissue growth factor (CTGF), a downstream mediator of transforming growth factor-␤1, mediates mesangial cell/fibroblast proliferation and extracellular matrix production by renal cells. Here, we show that renal tubular epithelial cells from patients with minimal change nephritic syndrome produced CTGF after glucocorticoid treatment. In addition, the glucocorticoid dexamethasone (DEX) increased CTGF mRNA levels in the kidneys of C57B6 but not SJL mice and produced intermediate CTGF mRNA levels in the kidneys of F1 (C57B6 ؋ SJL) mice, midway between the levels found for parental strains. DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA. Transient transfection experiments using luciferase reporter constructs bearing CTGF promoter fragments revealed that the ؊897-to ؊628-bp fragment contained DEX-responsive positive regulatory elements, which were active in mProx24 but not MCT cells. Long-term DEX treatment resulted in fibronectin deposition in the kidneys of C57B6 but not SJL mice, and this effect was inhibited by co-administration of CTGF anti-sense oligodeoxynucleotides. Thus, glucocorticoid-induced renal fibrogenesis seems to be influenced by genetic background, with the critical DEX-responsive elements in the ؊897-to ؊628-bp region of the CTGF promoter.

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Section: Discussionmentioning

confidence: 97%

Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner

Okada

Kikuta

Inoue

et al. 2006

The American Journal of Pathology

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“…This finding suggests that MP acts via the GCR to induce ADAMTS2. The GCR may act on transcription either indirectly or by binding to other transcription factors in an enhanceosome [42]. An enhanceosome is a complex consisting of transcription activators that promote the interaction and cooperative binding to the DNA and allows additive and synergistic effect on gene transcription [43].…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

et al. 2007

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The regulated expression of ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs), a secreted metalloproteinase involved in the processing of procollagen to collagen, was studied in peripheral blood mononuclear cells (PBMC). Stimulation with glucocorticoids (GC) resulted in a pronounced dose-and timedependent increase of ADAMTS2 mRNA levels in PBMC. The increase of ADAMTS2 expression was specific for CD14++ monocytes (440-fold) and alveolar macrophages (200-fold), whereas CD3+ (T lymphocytes), phytohemagglutinin-activated CD3+ (T lymphocytes), and CD19+ (B lymphocytes) showed no significant changes in ADAMTS2 mRNA after GC treatment. Treatment of monocyte-derived macrophages (MDM) with GC also resulted in an increase of ADAMTS2 protein in the culture tissue media. Using the GC analog RU486, GC-mediated induction of ADAMTS2 mRNA was blocked, implicating that GC acts specifically via the GCreceptor. In agreement with findings in blood monocytes, cell lines of the monocytic lineage (MM6, THP-1) showed significant GC-induced significant increases in ADAMTS2 mRNA, while in epithelial cells (A549, Calu-3, Colo320, BT-20) and fibroblast (MRC-5, WI-38, and two NHDF-c cell types from adult cheek and upper arm), they showed no or little responsiveness to GC. As macrophages have important functions in immune defense and tissue homeostasis, these findings suggest that GC-mediated specific induction of ADAMTS2 in these cells may play a crucial role in the resolution of inflammation and wound repair.

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“…The interaction of glucocorticoids with STAT3 have been described earlier for the regulation of genes like fibrinogen and alpha 2 macroglobulin (Duan and Simpson-Haidaris, 2006;Lerner et al, 2003;Takeda et al, 1998). In all these cases GCs do have little activity on their own but they operate synergistically with IL-6 induced STAT3.…”

Section: Discussionmentioning

confidence: 99%

Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene

Unterberger

Staples

Smallie³

et al. 2008

Molecular Immunology

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STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the α2-macroglobulin gene

Cited by 100 publications

References 46 publications

Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner

Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene

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