The involvement of p38 MAPK in transforming growth factor β1-induced apoptosis in murine hepatocytes

Liao, Jin Hui; Chen, Jun Song; Chai, Maofeng; Zhao, Sheng; Song, Jian

doi:10.1038/sj.cr.7290072

Cited by 55 publications

(40 citation statements)

References 30 publications

(50 reference statements)

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“…We have previously demonstrated that TGF-b1 induces the apoptosis of AML-12 hepatocytes via a mechanism involving the activation of p38 MAP kinase, 33 which was further confirmed and investigated in more detail by our recent study (data not shown). It has been reported that exogenous permeable ceramide analogs C 2 -ceramide and C 8 -ceramide induce the p38 phosphorylation.…”

Section: Of Three Experiments Performed In Duplicatessupporting

confidence: 60%

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

2003

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Serum deprivation induces apoptosis in NIH3T3 cells, which is associated with increased intracellular ceramide generation and with the activation of p38 mitogen-activated protein (MAP) kinase. Treatment of cells with transforming growth factor-b1 (TGF-b1) activated the extracellular signal regulated kinases 1 and 2 (ERK1/ERK2), inhibited the serum deprivation-induced p38 activation and the increase in intracellular ceramide formation, leading to the stimulation of cell proliferation and the suppression of apoptosis. Inhibition of p38 MAP kinase by SB203580 significantly reduced the serum-deprivation-induced apoptosis. Overexpression of p38 increased the cell apoptosis and reduced the antiapoptotic effect of TGF-b1. Inhibition of ERK1/ERK2 by PD98059 completely inhibited the TGF-b1-stimulated proliferation and partially inhibited the antiapoptotic effects of TGF-b1. Neither SB203580 nor PD98059 has obvious effect on TGF-b1-mediated inhibition of the increased ceramide generation. Serum-deprivation-induced apoptosis in NIH3T3 cells can also be blocked by broad-spectrum caspase inhibitor. TGF-b1 treatment has an inhibitory effect on caspase activities. Our results indicate that ceramide, p38, and ERK1/ERK2 play critical but differential roles in cell proliferation and stressinduced apoptosis. TGF-b1 suppresses the serum-deprivation-induced apoptosis via its distinct effects on complex signaling events involving the activation of ERK1/ERK2 and the inhibition of p38 activation and increased ceramide generation.

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Section: Of Three Experiments Performed In Duplicatessupporting

confidence: 60%

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

2003

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“…The p38 pathway has also been implicated in TGFbinduced cell death (Liao et al, 2001;Schrantz et al, 2001;Park et al, 2002;Yu et al, 2002), with use of an MKK3 dominant-negative construct or p38 inhibitors providing protection against TGFb-induced killing in some systems (Yu et al, 2002;Edlund et al, 2003;Yoo et al, 2003). However, there are cell type differences as to whether TGFb induces p38 activation and whether this is Smad-dependent or Smad-independent (Takekawa et al, 2002;Yu et al, 2002;Yoo et al, 2003), with early and late phases of p38 activation also likely employing different mechanisms.…”

Section: Resultsmentioning

confidence: 98%

Upregulation of two BH3-only proteins, Bmf and Bim, during TGFβ-induced apoptosis

et al. 2006

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“…Withdrawal of nerve growth factor from PC-12 cells has been shown to stimulate apoptosis in p38 MAP kinasedependent manner (52). Similarly p38 MAP kinase-dependent apoptosis has been shown in transforming growth factor-␤1-induced apoptosis in murine hepatocytes and in cytokine-induced rat islet cell apoptosis (7,46). Whether or not p38 MAP kinase plays any role in renal epithelial cell apoptosis following COM crystal exposure has not been evaluated and needs further study.…”

Section: Fig 5 Sb203580 Inhibits Com Crystal-induced Dna Synthesis mentioning

confidence: 99%

COM Crystals Activate the p38 Mitogen-activated Protein Kinase Signal Transduction Pathway in Renal Epithelial Cells

Koul¹,

Menon²,

Chaturvedi³

et al. 2002

Journal of Biological Chemistry

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Interaction of calcium oxalate monohydrate (COM) crystals with renal cells has been shown to result in altered gene expression, DNA synthesis, and cell death. In the current study the role of a stress-specific p38 MAP kinase-signaling pathway in mediating these effects of COM crystals was investigated. Exposure of cells to COM crystals (20 g/cm 2 ) rapidly stimulated strong phosphorylation and activation of p38 mitogen-activated protein kinase (p38 MAP kinase) and re-initiation of DNA synthesis. Inhibition of COM crystal binding to the cells by heparin blocked the effects of COM crystals on p38 MAPK activation. We also show that specific inhibition of p38 MAPK by 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl) imidazole (SB203580) or by overexpression of a dominant negative mutant of p38 MAP kinase abolishes COM crystal-induced re-initiation of DNA synthesis. The inhibition is dose-dependent and correlates with in situ activity of native p38 MAP kinase, determined as mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP kinase-2) activity in cell extracts. In summary, inhibiting activation of p38 MAPK pathway abrogated the DNA synthesis in response to COM crystals. These data are the first demonstrations of activation of the p38 MAPK signaling pathway by COM crystals and suggest that, in response to COM crystals, this pathway transduces critical signals governing the re-initiation of DNA synthesis in renal epithelial cells.Renal tubular fluid is commonly supersaturated with calcium and oxalate ions, which nucleate to form crystals of calcium oxalate monohydrate (COM), 1 the most common constituent of kidney stones. The majority of people do not form renal stones despite crystalluria (1). Up to 1.1 ϫ 10 7 crystals are excreted daily by normal individuals without any evidence of stone disease (2). It is therefore believed that uncomplicated crystalluria does not indicate kidney stone disease. The mechanisms by which urinary crystals are retained in the kidney and grow into kidney stones are not known. Finlayson (3) calculated that, given the most favorable conditions, it would take 10 h for 1-m COM crystals to grow large enough to block the duct of Bellini and become the nidus of a urinary stone. Because urinary transit time from glomerulus to the renal pelvis is ϳ3 min, crystalline particles formed in the urine flowing freely through the renal tubule do not stay in the lumen long enough to attain the dimensions required to block a collecting duct and form a urinary microlith. Therefore, the attachment of crystals to the renal epithelial cells and the cellular responses to crystal interaction are critical in understanding the pathogenesis of renal calcification.Previous studies (4 -6) in several different cell lines of renal tubular origin suggest that COM crystals bind to specific receptors on the cell surface. Furthermore, the receptors that interact with COM crystals in tubular cells may be only minimally exposed under normal circumstances and increase in number under a variety of cond...

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The involvement of p38 MAPK in transforming growth factor β1-induced apoptosis in murine hepatocytes

Cited by 55 publications

References 30 publications

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

Upregulation of two BH3-only proteins, Bmf and Bim, during TGFβ-induced apoptosis

COM Crystals Activate the p38 Mitogen-activated Protein Kinase Signal Transduction Pathway in Renal Epithelial Cells

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