Transforming Growth Factor-β1-Induced Activation of the Raf-MEK-MAPK Signaling Pathway in Rat Lung Fibroblasts via a PKC-Dependent Mechanism

Axmann, Andreas; Seidel, D.; Reimann, Thomas; Hempel, Ute; Wenzel, Klaus-Wolfgang

doi:10.1006/bbrc.1998.9188

Cited by 60 publications

(34 citation statements)

References 34 publications

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“…As demonstrated in Figure 3a, treatment of serum-starved PANC-1, BxPC-3, MIA PaCa-2, as well as NIH3T3 cells with medium containing 10 ng/ml EGF led to a signi®cant stimulation of ERK2 activity in all cell lines. Only in NIH3T3 ®broblasts addition of 10 ng/ml TGFb 1 for 15 min resulted in a signi®cant ERK2 activation (2.2-fold), which is in line with the results of TGFb 1 -mediated ERK activation in mesenchymal cells from other laboratories (Axmann et al, 1998;Reimann et al, 1997). Addition of TGFb 1 10 min before mitogenic stimulation (5 min with TGFb 1 plus EGF), resulted in marked reduction of EGFinduced MBP phosphorylation of PANC-1 (71%, To further characterize the in¯uence of TGFb 1 on growth factor-induced ERK2 activation, serum-starved PANC-1 and NIH3T3 cells were stimulated with serum.…”

Section: Tgfb 1 -Induced Inhibition Of Erk2supporting

confidence: 90%

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TGFβ1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation

et al. 2000

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Section: Tgfb 1 -Induced Inhibition Of Erk2supporting

confidence: 90%

“…In contrast to the epithelial cell system, mesenchymal cells respond dierently to TGFb as shown here and by others (Axmann et al, 1998;Reimann et al, 1997). To support the speci®city of the observed eects in epithelial PANC-1 and BxPC-3 cells, we analysed NIH3T3 cells for comparison.…”

Section: Discussionmentioning

confidence: 76%

TGFβ1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation

et al. 2000

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“…4 showed that TGF-␤1 activated AP-1 binding activity, which was also mediated by H 2 O 2 production. (32) and rat lung fibroblasts (33) and that MAPK is required for AP-1 activation (42). In HLF cells, FIGURE 8.…”

Section: Discussionmentioning

confidence: 98%

“…Evidences that TGF-␤1 is capable of activating MAPK pathways have been reported (32,33). We investigated the roles of MAPK/ ERK activation in TGF-␤1-induced IL-6 expression using an ERK kinase 1-specific inhibitor, PD98059.…”

Section: Requirement Of Mapk Activation In Tgf-␤1-induced Il-6 Expresmentioning

confidence: 99%

Requirement of Hydrogen Peroxide Generation in TGF-β1 Signal Transduction in Human Lung Fibroblast Cells: Involvement of Hydrogen Peroxide and Ca2+ in TGF-β1-Induced IL-6 Expression

Junn

Lee

et al. 2000

The Journal of Immunology

135

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Stimulation of human lung fibroblast cells with TGF-β1 resulted in a transient burst of reactive oxygen species with maximal increase at 5 min after treatment. This reactive oxygen species increase was inhibited by the antioxidant, N-acetyl-l-cysteine (NAC). TGF-β1 treatment stimulated IL-6 gene expression and protein synthesis in human lung fibroblast cells. Antioxidants including NAC, glutathione, and catalase reduced TGF-β1-induced IL-6 gene expression, and direct H2O2 treatment induced IL-6 expression in a dose-dependent manner. NAC also reduced TGF-β1-induced AP-1 binding activity, which is involved in IL-6 gene expression. It has been reported that Ca2+ influx is stimulated by TGF-β1 treatment. EGTA suppressed TGF-β1- or H2O2-induced IL-6 expression, and ionomycin increased IL-6 expression, with simultaneously modulating AP-1 activity in the same pattern. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-related kinase kinase 1, suppressed TGF-β1- or H2O2-induced IL-6 and AP-1 activation. In addition, TGF-β1 or H2O2 increased MAPK activity which was reduced by EGTA and NAC, suggesting that MAPK is involved in TGF-β1-induced IL-6 expression. Taken together, these results indicate that TGF-β1 induces a transient increase of intracellular H2O2 production, which regulates downstream events such as Ca2+ influx, MAPK, and AP-1 activation and IL-6 gene expression.

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“…TβRII binds TGF-β, stimulating association with ALK5/ TβRI and subsequent SMAD dependent and SMAD independent signaling (reviewed in [19][20][21][22][23][24][25]). SMAD dependent signaling has been the focus of TGF-β signaling studies since their discovery whereas SMAD independent signaling involving kinase cascades has more recently come to the fore as important in TGF-β influences [26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Gingery

Bradley

Pederson

et al. 2008

Experimental Cell Research

163

120

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To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX L expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

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Transforming Growth Factor-β1-Induced Activation of the Raf-MEK-MAPK Signaling Pathway in Rat Lung Fibroblasts via a PKC-Dependent Mechanism

Cited by 60 publications

References 34 publications

TGFβ1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation

TGFβ1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation

Requirement of Hydrogen Peroxide Generation in TGF-β1 Signal Transduction in Human Lung Fibroblast Cells: Involvement of Hydrogen Peroxide and Ca2+ in TGF-β1-Induced IL-6 Expression

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

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