Networking with mitogen-activated protein kinases

Pelech, Steven; Charest, David L.; Mordret, Guy; Siow, Yaw L.; Palaty, Chrystal K.; Campbell, Donna; Charlton, Lorin; Samiei, Mitra; Sanghera, Jasbinder S.

doi:10.1007/978-1-4615-2600-1_15

Cited by 13 publications

(17 citation statements)

References 126 publications

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“…G-protein substrates of pertussis toxin (PTx) were assayed using PTx-catalyzed incorporation of [ 32 P]adenosine diphosphate (ADP)-ribose from [ 32 P] nicotinamide adenine dinucleotide (NAD), as previously described. 19,35 Briefly, membranes (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) (100 ng/mL) was activated by prior incubation of 50 mmol/L HEPES (pH 8.0), containing 20 mmol/L DTT, 0.125% (wt/vol) SDS, and 0.1 mg/mL BSA for 30 minutes at room temperature. After addition of activated PTx (20 µg/mL), membrane preparations were incubated for 90 minutes at 30°C.…”

Section: Animalsmentioning

confidence: 99%

“…[20][21][22] MAPKs are ubiquitously expressed signaling cascades representing a key point of signal convergence from distinct transmembrane signaling pathways in the regulation of cell-cycle progression. 23,24 However, changes in expression and/or function of components of the MAPK cascade in tumor biology remain unclear at present. While the integral role of MAPKs in cellular proliferation is well documented, 23,24 recent reports using transformed cells from gastric carcinoma and colorectal adenocarcinoma demonstrated decreased MAPK activity in these tumors as compared with control tissue.…”

mentioning

confidence: 99%

“…23,24 However, changes in expression and/or function of components of the MAPK cascade in tumor biology remain unclear at present. While the integral role of MAPKs in cellular proliferation is well documented, 23,24 recent reports using transformed cells from gastric carcinoma and colorectal adenocarcinoma demonstrated decreased MAPK activity in these tumors as compared with control tissue. 25,26 In contrast, reports from our laboratory and others have identified increased MAPK expression in both human and animal models of HCC 27,28 and pretumorigenic hepatic conditions, 29,30 as well as in other nonhepatic tumors.…”

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confidence: 99%

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Enhanced Gi–Protein-Mediated Mitogenesis Following Chronic Ethanol Exposure in A Rat Model of Experimental Hepatocellular Carcinoma

et al. 1999

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Cirrhosis caused by chronic ethanol abuse remains a common clinical precursor to the development of hepatocellular carcinoma (HCC). 1,2 However, while clinical and epidemiological evidence linking alcohol abuse to HCC is compelling, mechanistic evidence directly linking chronic alcohol consumption to HCC development and/or progression in humans remains poor as a result of superimposed factors precluding unequivocal conclusions from being drawn. 2 This problem is in part a result of the inability to generate chronic ethanol-induced models of cirrhosis in vivo. 3 In addition, precise controls are difficult to produce because of the multiplicity of ethanol' s effects both on the liver and the organism as a whole. Previous reports have demonstrated that both chronic and acute exposure to ethanol act to alter normal hepatic functions, including carbohydrate and lipid metabolism, as well as protein and DNA synthesis. 4,5 Ethanol has been reported to affect the proliferation in hepatocytes in vitro and in vivo.

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Section: Animalsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Enhanced Gi–Protein-Mediated Mitogenesis Following Chronic Ethanol Exposure in A Rat Model of Experimental Hepatocellular Carcinoma

et al. 1999

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“…45,46 Of these, p21ras proteins have been the most extensively characterized and docuand nucleus following extracellular receptor activation. [6][7][8]38 Previous studies have reported that activation of MAPKs is mented. 18,47,48 Mutations of the p21ras protein have been identified in sufficient to transform NIH3T3 cells, 27,39,40 suggesting a potential role in the development and/or progression of tumori-numerous human tumors.…”

Section: Aid Hepa 0023mentioning

confidence: 99%

“…4 The mitogen-activated protein kinases (MAPKs) are a to constitutive activation of this protein and subsequent activation of downstream pathways including the MAPK cascade. group of ubiquitously expressed serine/threonine kinases 5,6 and represent a point of convergence for diverse signaling Using an in vivo model of hepatocellular carcinoma (HCC), we investigated the abundance and function of individual pathways originating at the cell membrane. 6-8 Activation of the MAPK cascade occurs rapidly following ligand binding components of the MAPK cascade and the presence of specific p21ras mutations in this model.…”

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Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma

et al. 1997

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The mitogen-activated protein kinase (MAPK) cascade acts regulation of cellular proliferation and differentiation of the normal hepatocyte. In the healthy liver, these pathways are as a focal point for signal transduction following activation of both G-protein-linked and tyrosine kinase growth factor tightly regulated processes by which constant liver mass and volume is maintained. 3 However, in the case of HCC, normal receptors. A common intermediate between both of these diverse receptor subtypes includes the small guanosine triphos-growth-promoting and growth-arresting components of the signal transduction circuitry become unbalanced, the net rephate (GTP)-binding protein, p21ras. Point mutations of p21ras have been identified in various tumor types and lead sult of which is uncontrolled hepatocyte growth. 4 The mitogen-activated protein kinases (MAPKs) are a to constitutive activation of this protein and subsequent activation of downstream pathways including the MAPK cascade. group of ubiquitously expressed serine/threonine kinases 5,6 and represent a point of convergence for diverse signaling Using an in vivo model of hepatocellular carcinoma (HCC), we investigated the abundance and function of individual pathways originating at the cell membrane. 6-8 Activation of the MAPK cascade occurs rapidly following ligand binding components of the MAPK cascade and the presence of specific p21ras mutations in this model. Expression of components to several distinct classes of cell surface receptors, 6,9,10 including G-protein-linked receptors [11][12][13] and tyrosine kinase of the MAPK cascade were determined in tumor and adjacent, non-neoplastic liver specimens by Western blot analysis and growth factor receptors. 14 Recent studies have identified the proto-oncogene, p21ras, as a common intermediate between functional activity confirmed by substrate phosphorylation assays. Mutations in p21ras were analyzed using an enzyme-both G-protein and tyrosine kinase-linked receptor activation and MAPK signaling. 14-16 Furthermore, point mutations linked immunosorbent assay. In tumor, extracellular regulated kinases (ERKs) ERK1, ERK2, and mitogen-activated of p21ras at either codon 12, 13, or 61 have been found to play an important role in the development of a variety of ERK-regulated kinase-1 (MEK1) were elevated by three-to fourfold as compared with adjacent nontumorigenic normal animal and human tumors. [17][18][19] The frequency of p21ras mutations in tumors varies widely between tumor types. Actiliver. In contrast, MEK2 was elevated by only 28%. Substrate vated p21ras genes are relatively rare in stomach and breast phosphorylation and detection of phosphorylated ERK1/2 tumors but are observed in 20% to 40% of lung carcinomas, proteins showed increased functional activity of these pro-30% of acute myelogenous leukemia, 40% to 50% of coloteins of the same magnitude as that observed for protein rectal tumors, and greater than 80% of pancreatic tumors. 14,20 expression. Mutations in p21ras were not detected in thisThe presen...

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Altered Gq/G11 Guanine Nucleotide Regulatory Protein Expression in A Rat Model of Hepatocellular Carcinoma: Role in Mitogenesis

et al. 1999

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Guanine nucleotide regulatory proteins (G-proteins) represent an important transmembrane pathway whereby extracellular signals are transduced to intracellular signaling pathways. The mitogen-activated protein kinase (MAPK) cascade has been identified as a key factor in transducing numerous mitogenic stimuli. MAPK activity is regulated via numerous receptor types, including those linked to Gq/G11-proteins, which regulate phospholipase-C activity. We hypothesized that alterations in a Gq/G11-PLC pathway may contribute to the enhanced cellular mitogenesis characteristic of hepatocellular carcinoma (HCC), possibly via a MAPK-dependent pathway. By using an in vivo model of HCC we investigated changes in Gq/G11-protein expression in tumorigenic tissue versus adjacent, non-neoplastic liver. In addition we addressed the role of Gq/G11-proteins in the regulation of MAPK-linked mitogenesis by using rat hepatic tumorigenic cells (H4IIE) and isolated hepatocytes in culture. Western blot analysis showed significant increases in Gq␣ and G11␣ expression in tumorigenic liver versus normal liver specimens, an effect that was augmented in cultured H4IIE cells versus isolated cultured hepatocytes. Furthermore, phosphoinositol specific phospholipase-C (PLC) activity was significantly increased in HCC versus normal liver. A specific PLC inhibitor (Et-18-OCH 3 ) caused a dose-dependent decrease in serum stimulated DNA synthesis in both cultured H4IIE cells and isolated rat hepatocytes, the H4IIE cell line showing greater sensitivity to Et-18-OCH 3 . In addition, serum-stimulated MAPK activity was significantly enhanced in H4IIE versus cultured hepatocytes. Moreover, treatment with Et-18-OCH 3 significantly attenuated serum stimulated MAPK activity in both cultured hepatocytes and H4IIE cells. Furthermore, U73122 (Gq␣-PLC specific uncoupler) and GP2A (Gq␣ specific inhibitor) mirrored the effects of those observed for Et-18-OCH 3 whereas PD98059 (specific MEK inhibitor) completely abolished serum-stimulated DNA synthesis in tumorigenic H4IIE cells. We conclude that HCC is associated with enhanced Gq/G11-PLC expression/activity as compared with normal liver. Furthermore, a PLC-linked MAPK cascade plays a significant role in the progression of the enhanced mitogenesis characteristic of HCC. (HEPATOL-OGY 1999;29:371-378.)

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Networking with mitogen-activated protein kinases

Cited by 13 publications

References 126 publications

Enhanced Gi–Protein-Mediated Mitogenesis Following Chronic Ethanol Exposure in A Rat Model of Experimental Hepatocellular Carcinoma

Enhanced Gi–Protein-Mediated Mitogenesis Following Chronic Ethanol Exposure in A Rat Model of Experimental Hepatocellular Carcinoma

Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma

Altered Gq/G11 Guanine Nucleotide Regulatory Protein Expression in A Rat Model of Hepatocellular Carcinoma: Role in Mitogenesis

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