TGF-β downregulates PTEN via activation of NF-κB in pancreatic cancer cells

Chow, Jennifer; Ban, Makiko; Wu, Helen L.; Nguyen, Flang; Huang, Mei; Chung, Heekyung; Dong, Hui; Carethers, John M.

doi:10.1152/ajpgi.00344.2009

Cited by 46 publications

(29 citation statements)

References 28 publications

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“…Furthermore, the fact that we did not observe NFB activation by TGF treatment of SMAD4-positive Panc1 cells is consistent with a recent report in the SMAD4-negative pancreatic cancer cell line BxPC3. Here, TGF-dependent activation of NFB is abolished by the re-expression of SMAD4 (Chow et al, 2010). However, the SMAD4-dependent mechanism blocking TGF-dependent NFB activation remains unclear at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

Brandl

Seidler

Haller

et al. 2010

Journal of Cell Science

116

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There was an error published in J. Cell Sci. 123, 4231-4239.In Fig. 4A, the cRel siRNA western blot panel was inadvertently constructed using the wrong images and all three western blots showed incorrect loading controls. The correct images and loading controls are shown in the figure below. The mistake in the figure did not affect the conclusions of the paper.We apologise for this mistake. . TGFb-dependent downregulation of E-cadherin is NFkB-independent. (A) Panc1 cells were transfected with a control or RelA/p65-, RelB-or c-Relspecific siRNA. At 24 hours after the transfection, cells were treated with 10 ng/ml TGFb or were left as an untreated control in DMEM without FCS. After an additional 48 hours, western blots detected RelA/p65, RelB or c-Rel and E-cadherin expression. The membrane was stripped and probed for a-tubulin or b-actin to ensure equal protein loading. (B) Panc1 (upper graph) and MDA-MB231 cells (lower graph) cells were co-transfected with a control or IKKa-specific siRNA and 500 ng of the pGL3control-, NFkB-or SMAD-luciferase reporter gene constructs as indicated. At 24 hours after the transfection, cells were treated with 10 ng/ml TGFb or were left as an untreated control. Luciferase activity was measured 6 hours after the TGFb treatment (Student's t-test: *P,0.05 versus control). (C) Panc1 (upper graph) and MDA-MB231 (lower graph) cells were transfected with a control or IKKa-specific siRNA. At 48 hours after the transfection, cells were stimulated with TGFb (10 ng/ml) for 20 minutes and binding of SMAD3 and SMAD4 to a SMAD consensus oligonucleotide was detected using ABCD assays. Input represents 5% of whole-cell extract of control siRNA-transfected cells. (D) Panc1 cells were treated as in C. Immunoprecipitation was performed with an IKKa-specific antibody or pre-immune serum as a control. Western blots of immunoprecipitates were probed with antibodies against IKKa and SMAD3. Input represents 5% of whole-cell extract of control siRNA-transfected Panc1 cells. (E) MDA-MB231 cells were transfected with a control or IKKa-specific siRNA. At 24 hours after the transfection, cells were treated with 10 ng/ml TGFb or were left as an untreated control in DMEM without FCS. After an additional 48 hours, western blots detected IKKa expression. The membrane was stripped and probed for b-actin to ensure equal protein loading.

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Section: Discussionmentioning

confidence: 99%

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

Brandl

Seidler

Haller

et al. 2010

Journal of Cell Science

116

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“…78,79 (v) It has been clearly demonstrated that the action of TGF-b is induced through the activation of NF-kB. 25,26,75,76,80,81 At the same time, it has been reported that NF-kB activation induces TGF-b production. [82][83][84] Thus, there is a potential positive feedback mechanism between TGF-b production and NF-kB activation that enhances the fibrotic process.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

123

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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“…It is established that activation of NF-B results in downregulation of PTEN expression (38)(39)(40). The downregulation of PTEN leads to increased recruitment of macrophages and elevated levels of proinflammatory cytokines and chemokines in inflamed lungs, which, in turn, is thought to induce increased neutrophil recruitment to the lungs.…”

Section: Discussionmentioning

confidence: 99%

Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

et al. 2013

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cFus1 is a tumor suppressor protein with recently described immunoregulatory functions. Although its role in sterile inflammation is being elucidated, its role in regulating immune responses to infectious agents has not been examined. We used here a murine model of Acinetobacter baumannii pneumonia to identify the role of Fus1 in antibacterial host defenses. We found that the loss of Fus1 in mice results in significantly increased resistance to A. baumannii pneumonia. We observed earlier and more robust recruitment of neutrophils and macrophages to the lungs of infected Fus1 ؊/؊ mice, with a concomitant increase in phagocytosis of invading bacteria and more rapid clearance. Such a prompt and enhanced immune response to bacterial infection in Fus1 ؊/؊ mice stems from early activation of proinflammatory pathways (NF-B and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin [mTOR]), most likely due to significantly increased mitochondrial membrane potential and mitochondrial reactive oxygen species production. Significant early upregulation of interleukin-17 (IL-17) in Fus1 ؊/؊ immune cells was also observed, together with significant downregulation of IL-10. Depletion of neutrophils eliminates the enhanced antibacterial defenses of the Fus1 ؊/؊ mice, suggesting that ultimately it is the enhanced immune cell recruitment that mediates the increased resistance of Fus1 ؊/؊ mice to A. baumannii pneumonia. Taken together, our data define the novel role for Fus1 in the immune response to A. baumannii pneumonia and highlight new avenues for immune modulating therapeutic targets for this treatment-resistant nosocomial pathogen.

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TGF-β downregulates PTEN via activation of NF-κB in pancreatic cancer cells

Cited by 46 publications

References 28 publications

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

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