Inhibition of MAP Kinase Kinase Blocks the Differentiation of PC-12 Cells Induced by Nerve Growth Factor

Pang, Long; Sawada, Takeshi; Decker, Stuart J.; Saltiel, Alan R.

doi:10.1074/jbc.270.23.13585

Cited by 854 publications

(654 citation statements)

References 33 publications

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“…Identical data were obtained measuring Raf-1\B-Raf activities using stimulated MEK1 activity versus kinase inactive K52R p42 MAPkinase (data not shown). Treatment of hepatocytes with EGF also induced an acute phasic activation of the MAP kinase cascade ( Figure 2B), in agreement with data in [36]. In doseresponse studies, maximal activation of the MAP kinase cascade in primary cultures of hepatocytes by NGF treatment occurred at 10-20 ng\ml (" 0n8 nM) with a half maximal activation at " 3 ng\ml (" 0n25 nM) ( Figure 2C).…”

Section: Ngf Treatment Chronically Activates the Map Kinase Cascade Isupporting

confidence: 89%

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Tombes

Auer

Mikkelsen

et al. 1998

Biochemical Journal

179

155

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Bailie et al. [In Vitro Cell Dev. Biol. (1992) 28A, 621-624] reported that primary cultures of rat hepatocytes possess low affinity binding sites for nerve growth factor (NGF). NGF treatment of primary cultures of rat hepatocytes with a maximally effective concentration of NGF (20 ng/ml, 0.8 nM) caused acute phasic activation of Raf-1 and p42MAPkinase, and a smaller sustained activation of B-Raf. The transient increase in Raf-1 and p42MAPkinase activity returned to baseline within ~ 30 min. NGF treatment of hepatocytes did not induce expression of cyclin dependent kinase (cdk) inhibitor proteins, but instead stimulated cdk2 activity and increased [3H]thymidine incorporation into DNA. In contrast to hepatocytes, NGF treatment of PC12 pheochromocytoma cells caused large sustained activations of B-Raf and p42MAPkinase, and a lower phasic activation of Raf-1. The sustained activations of B-Raf and p42MAPkinase were for more than 5 h. Treatment of PC12 cells with NGF increased p21Cip1/WAF-1 expression, reduced cdk2 activity and inhibited DNA synthesis, the opposite to the effects of NGF treatment of hepatocytes. However when p42MAPkinase was chronically activated in hepatocytes, via infection with an inducible oestrogen receptor-Raf-1 fusion protein, expression of p21Cip-1/WAF1 and p16INK4a cdk inhibitor proteins increased, cdk2 activity decreased, and DNA synthesis decreased. Equally, treatment of hepatocytes with 50 mM ethanol elevated the basal activity of p42MAPkinase and temporally extended the ability of NGF treatment to activate p42MAPkinase. Ethanol and NGF co-treatment increased expression of p21Cip-1/WAF1 and p16INK4a cdk inhibitor proteins and decreased hepatocyte DNA synthesis. These data demonstrate that NGF can cause either acute/phasic or sustained activation of the MAP kinase cascade in different cell types. Acute activation of the MAP kinase cascade correlated with increased DNA synthesis. In contrast, sustained activation of the MAP kinase cascade correlated with increased expression of cdk inhibitor proteins, a reduction in cdk activity, and an inhibition of DNA synthesis. These data suggest a general mechanism exists where acute activation of the MAP kinase cascade promotes G1 progression/S phase entry and that chronic activation of the MAP kinase cascade inhibits this process.

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Section: Ngf Treatment Chronically Activates the Map Kinase Cascade Isupporting

confidence: 89%

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Tombes

Auer

Mikkelsen

et al. 1998

Biochemical Journal

179

155

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“…MAP kinase activation in adipocytes [7] or PC12 cells [21], respectively, PD98059 blocked activation of p42 mapk following treatment with thrombin, histamine, inflammatory cytokines or pervanadate. In agreement with previously published reports [6] the degree of inhibition depended upon the strength of p42 mapk activation; thus, 5 p~M PD98059 abolished p42 m~pk activation induced by maximally effective doses of thrombin, histamine, or IL-lc¢ whereas 10-fold higher concentrations were required to suppress activation induced by pervanadate (not shown) which promotes a near complete shift of p42 mapk to its phosphorylated, active form.…”

Section: Discussionmentioning

confidence: 88%

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

et al. 1996

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We have examined the potential role of MAP kinase in the regulation of endothelial cell PGI2 synthesis, vWF secretion and E-selectin expression using the specific MEK inhibitor PD98059. PD98059 dose-dependently attenuated the tyrosine phosphorylation and activation of !}42 mapk in response to thrombin or inflammatory cytokines. Inhibition of thrombinmapk induced p42 activation was paralleled by an inhibitory effect of PD98059 on thrombin-driven PGI2 generation but not on vWF secretion or IL-lo0TNF~-induced E-selectin expression. These results provide evidence for a key role for !142 mapk in the acute regulation of PGI2 synthesis in human endothelial cells and suggest that activation of the MAP kinase cascade is not obligatory for cytokine-stimulated E-selectin expression.

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“…We have provided three lines of evidences which suggest that EGF modulates the survival of CE81T/VGH cells through the activation of the Raf-MEK-ERK pathway. The speci®c MEK inhibitor PD98059 (Alessi et al, 1995;Pang et al, 1995) suppressed the anti-apoptotic e ect of EGF on staurosporine-treated cells (Figure 3b), implying the involvement of MEK-ERK pathway. In addition, transiently transfected ERK2 DN mutant suppressed the protective e ect of EGF (Figure 4d).…”

Section: Discussionmentioning

confidence: 94%

Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway

Leu¹,

Chang²,

Hu³

2000

Oncogene

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Overexpression of epidermal growth factor receptor (EGFR) and establishment of transforming growth factor a (TGF a)/EGF autocrine system are frequently detected in tumor cells. In addition to mitogenic ability, we demonstrate in this report that EGF protects a human esophageal carcinoma (CE) cell line, CE81T/VGH, from staurosporine-induced apoptosis. The anti-apoptotic signal of EGF is alleviated by a MEK inhibitor PK98059 or an ERK2 dominant negative mutant but not by a phosphatidylinositol-3'-kinase (PI-3K) inhibitor wortmannin. Furthermore, v-raf blocks apoptosis induced by staurosporine. This evidence implies that the survival signal of EGF is mediated via the Raf-MEK-ERK pathway but not the PI3-K pathway. The survival e ect of EGF is coincident with the induction of mcl-1, an antiapoptotic gene in the bcl-2 family. PD98059 also suppresses the induction of Mcl-1 by EGF, implying that EGF may up-regulate Mcl-1 via the MAP kinase pathway. Overexpression of mcl-1 is su cient to protect against apoptosis, while transfection of a mcl-1 antisense plasmid causes cell death. The expression of mcl-1 antisense plasmid also suppresses the anti-apoptotic e ect of EGF. Taken together, these results indicate that EGF may up-regulate Mcl-1 through the MAP kinase pathway to suppress apoptosis.

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Inhibition of MAP Kinase Kinase Blocks the Differentiation of PC-12 Cells Induced by Nerve Growth Factor

Cited by 854 publications

References 33 publications

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway

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Inhibition of MAP Kinase Kinase Blocks the Differentiation of PC-12 Cells Induced by Nerve Growth Factor

Cited by 854 publications

References 33 publications

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI2 release but has no effect on von Willebrand factor secretion or E‐selectin expression

Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway

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Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression