Rat Mrp2 gene expression is regulated by an interleukin-1β-stimulated biphasic response with enhanced transcription and subcellular shuttling of YB-1

Mertens, Peter R.; Martin, Ina V.; Frye, Björn C.; Rauen, Thomas; Strauch, S.; Pabst, Melanie; Geier, Andreas

doi:10.1016/j.ejcb.2011.12.002

Cited by 10 publications

(4 citation statements)

References 44 publications

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“…How is YBX1 distributed in cells? Nuclear shuttling of YBX1 has been associated with its increased tumor promoter activity, and has been shown to occur upon stimulation with IL-1β [ 22 ]. In order to establish if phosphorylation at S165 is important for the nuclear shuttling of YBX1, we carried out an immunofluorescence [IF] experiment to check for Flag-tagged YBX1 localization.…”

Section: Resultsmentioning

confidence: 99%

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

et al. 2015

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Y-box binding protein 1 [YBX1] is a multifunctional protein known to facilitate many of the hallmarks of cancer. Elevated levels of YBX1 protein are highly correlated with cancer progression, making it an excellent marker in cancer. The connection between YBX1 and the important nuclear factor κB [NF-κB] has never been reported. Here, we show that overexpression of wild type YBX1 [WT-YBX1] activates NF-κB, suggesting that YBX1 is a potential NF-κB activator. Furthermore, using mass spectrometry analysis we identified novel phosphorylation of serine 165 [S165] on YBX1. Overexpression of the S165A-YBX1 mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB activating ability as compared with that of WT-YBX1, confirming that S165 phosphorylation is critical for the activation of NF-κB by YBX1. We also show that expression of the S165A-YBX1 mutant dramatically decreased the expression of NF-κB-inducible genes, reduced cell growth, and compromised tumorigenic ability as compared with WT-YBX1. Taken together, we provide the first evidence that YBX1 functions as a tumor promoter via NF-κB activation, and phosphorylation of S165 of YBX1 is critical for this function. Therefore, our important discovery may lead to blocking S165 phosphorylation as a potential therapeutic strategy to treat colon cancer.

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Section: Resultsmentioning

confidence: 99%

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

et al. 2015

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“…A transient upregulation of YB-1 protein occurs during experimental mesangioproliferative nephritis (13), especially in the acute proliferative phase, and YB-1 predominantly localizes to the mesangial compartment. In other studies, LPS exposure induced YB-1 expression in the fetal brain (26) and liver (27). Furthermore, in hearts recovering from ischemia/ reperfusion injury, YB-1 upregulation occurred transiently in a situation of sterile inflammation (4).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously demonstrated that YB-1 is involved in the onset of inflammation (4,(26)(27)(28). A transient upregulation of YB-1 protein occurs during experimental mesangioproliferative nephritis (13), especially in the acute proliferative phase, and YB-1 predominantly localizes to the mesangial compartment.…”

Section: Discussionmentioning

confidence: 99%

YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

Hanssen

Alidousty

Djudjaj

et al. 2013

The Journal of Immunology

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In vitro studies identified Y-box–binding protein (YB)-1 as a key regulator of inflammatory mediators. In this study, we observed increased levels of secreted YB-1 in sera from sepsis patients. This led us to investigate the in vivo role of YB-1 in murine models of acute peritonitis following LPS injection, in sterile renal inflammation following unilateral ureteral obstruction, and in experimental pyelonephritis. LPS injection enhanced de novo secretion of YB-1 into the urine and the peritoneal fluid of LPS-treated mice. Furthermore, we could demonstrate a significant, transient upregulation and posttranslational modification (phosphorylation at serine 102) of YB-1 in renal and inflammatory cells. Increased renal cytoplasmic YB-1 amounts conferred enhanced expression of proinflammatory chemokines CCL2 and CCL5. Along these lines, heterozygous YB-1 knockout mice (YB-1+/d) that display 50% reduced YB-1 levels developed significantly lower responses to both LPS and sterile inflammation induced by unilateral ureteral obstruction. This included diminished immune cell numbers due to impaired migration propensities and reduced chemokine expression. YB-1+/d mice were protected from LPS-associated mortality (20% mortality on day 3 versus 80% in wild-type controls); however, immunosuppression in YB-1+/d animals resulted in 50% mortality. In conclusion, our findings identify YB-1 as a major, nonredundant mediator in both systemic and local inflammatory responses.

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“…Considering the limited information on the mechanisms regulating YB-1 expression [42], the basis for the effects of IRAK-M loss on YB-1 levels remains unclear. Pro-inflammatory cytokines (such as IL-1β) are upregulated in the absence of IRAK-M, and are known to induce YB-1 transcription and activation [43]. Moreover, MAPKs have been implicated in regulation and activation of YB-1 [44].…”

Section: Discussionmentioning

confidence: 99%

The role of Interleukin Receptor Associated Kinase (IRAK)-M in regulation of myofibroblast phenotype in vitro, and in an experimental model of non-reperfused myocardial infarction

Saxena

Shinde

Haque

et al. 2015

Journal of Molecular and Cellular Cardiology

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In the infarcted myocardium, necrotic cardiomyocytes activate innate immune pathways, stimulating pro-inflammatory signaling cascades. Although inflammation plays an important role in clearance of the infarct from dead cells and matrix debris, repair of the infarcted heart requires timely activation of signals that negatively regulate the innate immune response, limiting inflammatory injury. We have previously demonstrated that Interleukin receptor-associated kinase (IRAK)-M, a member of the IRAK family that suppresses toll-like receptor/interleukin-1 signaling, is upregulated in the infarcted heart in both macrophages and fibroblasts, and restrains pro-inflammatory activation attenuating adverse remodeling. Although IRAK-M is known to suppress inflammatory activation of macrophages, its role in fibroblasts remains unknown. Our current investigation examines the effects of IRAK-M on fibroblast phenotype and function. In vitro, IRAK-M null cardiac fibroblasts have impaired capacity to contract free-floating collagen pads. IRAK-M loss reduces transforming growth factor (TGF)-β-mediated α-smooth muscle actin (α-SMA) expression. IRAK-M deficient cardiac fibroblasts exhibit a modest reduction in TGF-β-stimulated Smad activation and increased expression of the α-SMA repressor, Y-box binding protein (YB)-1. In a model of non-reperfused myocardial infarction, IRAK-M absence does not affect collagen content and myofibroblast density in the infarcted and remodeling myocardium, but increases YB-1 levels and is associated with attenuated α-SMA expression in isolated infarct myofibroblasts. Our findings suggest that, in addition to its role in restraining inflammation following reperfused infarction, IRAK-M may also contribute to myofibroblast conversion.

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Rat Mrp2 gene expression is regulated by an interleukin-1β-stimulated biphasic response with enhanced transcription and subcellular shuttling of YB-1

Cited by 10 publications

References 44 publications

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer

YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

The role of Interleukin Receptor Associated Kinase (IRAK)-M in regulation of myofibroblast phenotype in vitro, and in an experimental model of non-reperfused myocardial infarction

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