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Grigorov, Ilijana; Lazić, T; Cvetković, Ivana; Milosavljevic, Tanja; Petrović, M.

doi:10.1023/a:1015749109119

Cited by 6 publications

(1 citation statement)

References 26 publications

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“…STAT5a/b are transcription factors regulated by a wide variety of cytokines such as interleukins. Importantly, consistent with the results in our study, published literature shows that in response to turpentine-induced inflammation in rats, Stat5b protein level is reduced in the nucleus of the liver 12 hours after injection [20]. The mechanism(s) by which inflammatory cytokines decrease Stat5 signaling remain to be elucidated.…”

Section: Discussionsupporting

confidence: 92%

Inflammation Regulates TMPRSS6 Expression via STAT5

Meynard

Sun

et al. 2013

PLoS ONE

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TMPRSS6 is a regulated gene, with a crucial role in the regulation of iron homeostasis by inhibiting hepcidin expression. The main regulator of iron homeostasis, the antimicrobial peptide hepcidin, which also has a role in immunity, is directly upregulated by inflammation. In this study, we analyzed whether inflammation is also a modulator of TMPRSS6 expression in vitro and in vivo and we determined the mechanism of this regulation A Human Hepatoma cell line was treated with interleukin-6 and mice were injected with lipopolysaccharide and TMPRSS6 expression and the regulatory mechanism were addressed. In this study, we demonstrate that inflammation downregulates TMPRSS6 expression in vitro and in vivo. The downregulation of Tmprss6 by inflammation in mice is not dependent on the Bmp-Smad pathway but occurs through a decrease in Stat5 phosphorylation. Moreover, Stat5 positively regulates Tmprss6 expression directly by binding to a Stat5 element located on the Tmprss6 promoter. Importantly, our results highlight the functional role of inflammatory modulation of TMPRSS6 expression in the regulation of hepcidin. TMPRSS6 inhibition via decreased STAT5 phosphorylation may be an additional mechanism by which inflammation stimulates hepcidin expression to regulate iron homeostasis and immunity.

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Section: Discussionsupporting

confidence: 92%

Inflammation Regulates TMPRSS6 Expression via STAT5

Meynard

Sun

et al. 2013

PLoS ONE

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Association of the glucocorticoid receptor with STAT3, C/EBPβ, and the hormone‐responsive element within the rat haptoglobin gene promoter during the acute phase response

et al. 2010

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SummaryUpregulation of haptoglobin (Hp) expression in the rat during the acute phase (AP) response is the result of synergistic effects of IL-6-, IL-1b-, and corticosterone-activated signaling pathways. IL-6 signaling terminates in cis-trans interactions of the Hp gene hormone-responsive element (HRE) with transcription factors STAT3 and C/EBPb. The aim of this study was to examine the unresolved molecular mechanism of glucocorticoid action. A 3-fold rise in serum corticosterone at 2 and 4 h of the AP response induced by turpentine administration preceded a 2.3-fold increase in the rate of Hp gene transcription at 12 h that was accompanied by a 4.8-fold increase in glucocorticoid receptor (GR), the appearance of an 86-kDa STAT3 isoform and 3.9-, 1.9-, and 1.7-fold increased amounts of 91-kDa STAT3, 35-and 42-kDa C/EBPb isoforms in the nucleus. These events resulted in 4.6-and 2.5-fold increased Hp levels in the liver and serum at 24 h. HRE affinity chromatography and immunoblot analysis revealed that maximal occupancy of the HRE with GR, STAT3, and C/EBPb at 12 h correlated with increased transcriptional activity of the Hp gene. Coimmunoprecipitation experiments showed that activated GR established de novo interaction with STAT3 isoforms while GR-C/EBPb interactions observed during basal transcription increased during the AP response. Computer analysis of the HRE disclosed two potential GR-binding sites: one overlapping STAT3, another adjacent to a C/EBPb-binding site. This finding and the experimental results suggest that activated GR through direct interactions with STAT3 and C/EBPb, participates in Hp gene upregulation as a transcriptional coactivator.

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Regulation of rat haptoglobin gene expression is coordinated by the nuclear matrix

Vidaković¹,

Dinić²,

Grdović³

et al. 2009

J of Cellular Biochemistry

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Using computer stress-induced duplex destabilization (SIDD) analysis and binding experiments, we identified a S/MAR element (-599/-200 bp) (Hp-S/MAR) adjacent to the cis-element (-165/-56 bp) in the rat haptoglobin gene. We examined its functional interactions with the lamins and lamin-associated proteins in the basal state and during acute-phase (AP) response-induced increased transcription. Colocalization, electrophoretic mobility shift assay (EMSA), and re-electrophoresis of nucleoprotein complexes, South-Western and Western blot analysis and coimmunoprecipitation experiments revealed that the lamins, PARP-1, C/EBP beta, and Hp-S/MAR assembled higher order complexes through direct lamin-Hp-S/MAR and probably PARP-1-Hp-S/MAR interactions although C/EBP beta did not bind to the Hp-S/MAR but established direct interaction with PARP-1. The transition from constitutive to increased haptoglobin gene transcription during the AP response was associated with quantitative and qualitative changes in Hp-S/MAR-protein interactions, respectively, observed as increased association of the lamin(s) with the Hp-S/MAR and as the appearance of a 90 kDa Hp-S/MAR-binding protein. Also, during the AP response the contact between C/EBP beta and PARP-1 established in the basal state was lost. DNA chromatography with the haptoglobin cis-element and Western blot analysis suggests that PARP-1 was a coactivator during constitutive and elevated transcription. The results show that the lamin components of the nuclear matrix form a network of functional, dynamic protein-protein and protein-Hp-S/MAR associations with multiple partners, and underline the involvement of PARP-1 in the regulation of haptoglobin gene transcription. We concluded that the interplay of these interactions fine tunes haptoglobin gene expression to meet the changing requirements of liver cells.

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Cited by 6 publications

References 26 publications

Inflammation Regulates TMPRSS6 Expression via STAT5

Inflammation Regulates TMPRSS6 Expression via STAT5

Association of the glucocorticoid receptor with STAT3, C/EBPβ, and the hormone‐responsive element within the rat haptoglobin gene promoter during the acute phase response

Regulation of rat haptoglobin gene expression is coordinated by the nuclear matrix

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