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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR) and the mitogen-activated protein kinase (MAPK) pathway can promote tumor cell survival in response to cytotoxic insults. In this study, we examined the impact of MAPK signaling on the survival of primary hepatocytes exposed to low concentrations of deoxycholic acid (DCA, 50 microM). Treatment of hepatocytes with DCA caused MAPK activation, which was dependent upon ligand independent activation of EGFR, and downstream signaling through Ras and PI(3) kinase. Neither inhibition of MAPK signaling alone by MEK1/2 inhibitors, nor exposure to DCA alone, enhanced basal hepatocyte apoptosis, whereas inhibition of DCA-induced MAPK activation caused approximately 25% apoptosis within 6 h. Similar data were also obtained when either dominant negative EGFR-CD533 or dominant negative Ras N17 were used to block MAPK activation. DCA-induced apoptosis correlated with sequential cleavage of procaspase 8, BID, procaspase 9, and procaspase 3. Inhibition of MAPK potentiated bile acid-induced apoptosis in hepatocytes with mutant FAS-ligand, but did not enhance in hepatocytes that were null for FAS receptor expression. These data argues that DCA is causing ligand independent activation of the FAS receptor to stimulate an apoptotic response, which is counteracted by enhanced ligand-independent EGFR/MAPK signaling. In agreement with FAS-mediated cell killing, inhibition of caspase function with the use of dominant negative Fas-associated protein with death domain, a caspase 8 inhibitor (Ile-Glu-Thr-Asp-p-nitroanilide [IETD]) or dominant negative procaspase 8 blocked the potentiation of bile acid-induced apoptosis. Inhibition of bile acid-induced MAPK signaling enhanced the cleavage of BID and release of cytochrome c from mitochondria, which were all blocked by IETD. Despite activation of caspase 8, expression of dominant negative procaspase 9 blocked procaspase 3 cleavage and the potentiation of DCA-induced apoptosis. Treatment of hepatocytes with DCA transiently increased expression of the caspase 8 inhibitor proteins c-FLIP-(S) and c-FLIP-(L) that were reduced by inhibition of MAPK or PI(3) kinase. Constitutive overexpression of c-FLIP-(s) abolished the potentiation of bile acid-induced apoptosis. Collectively, our data argue that loss of DCA-induced EGFR/Ras/MAPK pathway function potentiates DCA-stimulated FAS-induced hepatocyte cell death via a reduction in the expression of c-FLIP isoforms.
Mol Biol Cell 2001 Sep
PMID:Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. 1155 4

Herein, we investigated the activity of mitogen-activated protein kinase (MAPK), a key component of downstream signaling events, which is activated subsequent to platelet-derived growth factor (PDGF)-BB stimulation. Specifically, p42(MAPK) activity peaked 60 min after addition of PDGF-BB, declined thereafter, and was determined not to be a direct or necessary component of glycosaminoglycan (GAG) synthesis. PDGF-BB also activated MAPK kinase 2 (MAPKK2) but had no effect on MAPKK1 and Raf-1 activity. Chemical inhibition of Janus kinase, phosphatidylinositol 3-kinase, Src kinase, or tyrosine phosphorylation inhibition of the PDGF beta-receptor (PDGFR-beta) did not abrogate PDGF-BB-induced p42(MAPK) activation or its threonine or tyrosine phosphorylation. A dominant negative cytoplasmic receptor for hyaluronan-mediated motility variant 4 (RHAMMv4), a regulator of MAPKK-MAPK interaction and activation, did not inhibit PDGF-BB-induced p42(MAPK) activation nor did a construct expressing PDGFR-beta with cytoplasmic tyrosines mutated to phenylalanine. However, overexpression of a dominant negative PDGFR-beta lacking the cytoplasmic signaling domain abrogated p42(MAPK) activity. These results suggest that PDGF-BB-mediated activation of p42(MAPK) requires the PDGFR-beta but is independent of its tyrosine phosphorylation.
Am J Physiol Lung Cell Mol Physiol 2001 Oct
PMID:PDGF-BB-mediated activation of p42(MAPK) is independent of PDGF beta-receptor tyrosine phosphorylation. 1155 82

The zinc finger-containing transcription factor GATA4 has been implicated as a critical regulator of multiple cardiac-expressed genes as well as a regulator of inducible gene expression in response to hypertrophic stimulation. Here we demonstrate that GATA4 is itself regulated by the mitogen-activated protein kinase signaling cascade through direct phosphorylation. Site-directed mutagenesis and phospho-specific GATA4 antiserum revealed serine 105 as the primary site involved in agonist-induced phosphorylation of GATA4. Infection of cultured cardiomyocytes with an activated MEK1-expressing adenovirus induced robust phosphorylation of serine 105 in GATA4, while a dominant-negative MEK1-expressing adenovirus blocked agonist-induced phosphorylation of serine 105, implicating extracellular signal-regulated kinase (ERK) as a GATA4 kinase. Indeed, bacterially purified ERK2 protein directly phosphorylated purified GATA4 at serine 105 in vitro. Phosphorylation of serine 105 enhanced the transcriptional potency of GATA4, which was sensitive to U0126 (MEK1 inhibitor) but not SB202190 (p38 inhibitor). Phosphorylation of serine 105 also modestly enhanced the DNA binding activity of bacterially purified GATA4. Finally, induction of cardiomyocyte hypertrophy with an activated MEK1-expressing adenovirus was blocked with a dominant-negative GATA4-engrailed-expressing adenovirus. These results suggest a molecular pathway whereby MEK1-ERK1/2 signaling regulates cardiomyocyte hypertrophic growth through the transcription factor GATA4 by direct phosphorylation of serine 105, which enhances DNA binding and transcriptional activation.
Mol Cell Biol 2001 Nov
PMID:The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. 1158 26

Raf-1, a key kinase in the Ras signaling pathway, plays critical roles in cell differentiation, proliferation, and tumorigenesis. However, knowledge of the Raf-1 in inflammation is limited. Using an inducible oncogenic Raf-1, we show that the Raf-1 orchestrates the discrete NF-kappaB activating pathways. While the Raf-1 activation induces a modest IkappaB degradation by enhancing the basal IkappaB kinase activity, it contradictorily suppresses the proinflammatory cytokine inducible IkappaB kinase complex, leading to an inhibition of TNF-alpha- and IL-1beta-induced NF-kappaB activation. Despite considerable degrees of overlap, LPS signaling is not affected by Raf-1. By either conditionally reducing Raf-1 activity or completely disrupting the Raf-1 signaling by PD98059, a specific inhibitor of MEK1, the otherwise inhibited cytokine responses can be restored. Moreover, when the activity of Raf-1 is up-regulated during the cell cycle progression from the G(0) phase to the late G(1) phase, the enhanced Raf-1 activity suffices to shift the TNF-alpha response from the sensitive to the insensitive state. Together, these studies elucidate a mechanism by which signaling outputs are shaped by the intracellular Raf-1, thus explaining the "cellular context"-dependent cytokine response.
Mol Cell Biol Res Commun 2001 Nov
PMID:Role of the oncogenic Raf-1 in orchestration of discrete nuclear factor-kappaB-activating pathways. 1170 98

Pulmonary fibrosis is a progressive disorder characterized by the loss of alveolar architecture through epithelial and endothelial cell apoptosis and fibroblast proliferation. Recent studies showed that angiotensin-converting enzyme (ACE) activity is increased in fibrotic tissues, and ACE inhibitors administered in vivo ameliorate fibrosis, suggesting that ACE may play a critical role. However, the regulation of ACE expression is not well understood. In the present study, we demonstrate that bleomycin, a chemotherapeutic agent which induces pulmonary fibrosis in animals and humans, increases gene expression of ACE. Treatment of primary bovine pulmonary artery endothelial cells with 0.1 to 1.0 microg/ml bleomycin increased ACE enzymatic activity and ACE mRNA, as monitored by hippuryl-L-histidyl-L-leucine assay and competitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Luciferase reporter constructs showed that upregulation of ACE transcription by bleomycin is mediated through element(s) in the 97-bp ACE promoter. Bleomycin activated p42/p44 mitogen-activated protein kinase (MAPK) and induced nuclear translocation and activation of the early growth response (Egr)-1 transcription factor, a factor previously shown to positively regulate ACE expression. The MAPK kinase1/2 (MEK1/2) inhibitor U0126 blocked MAPK and Egr-1 activation by bleomycin, suggesting that Egr-1 activation is MAPK dependent. These data provide the first evidence that bleomycin activates ACE gene expression through the MAPK pathway and Egr-1.
Am J Respir Cell Mol Biol 2001 Nov
PMID:Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor. 1171 4

Proliferation of bronchial epithelial cells is an important biologic process in a variety of physiologic and pathologic conditions. In this study, we demonstrate that hepatocyte growth factor (HGF) stimulates proliferation of human bronchial epithelial cells obtained from healthy volunteers. The mitogenic effect of HGF is dependent on costimulation with serum and is completely abrogated by interferon-gamma (IFN-gamma). In the absence of serum, HGF is capable of inducing activation of extracellular signal-regulated kinases (ERK)1 and ERK2, but fails to stimulate proliferation by itself. These effects of HGF and IFN-gamma were reproduced faithfully in BEAS-2B cells, which are an immortalized cell line derived from human bronchial epithelial cells. Further, we investigated the molecular mechanisms underlying the effects of HGF and IFN-gamma in BEAS-2B cells and found that the MEK1 inhibitor PD98059, but not the p38 M-associated protein kinase inhibitor SB203580, abrogates HGF-induced ERK activation and proliferation in response to HGF and serum. In addition, LY294002, which is the specific inhibitor of phosphatidyl inositol 3-kinase, partially inhibited HGF- and serum-stimulated proliferation. We also found that HGF by itself is capable of inducing a G1 cyclin, cyclin D1, but fails to downregulate p27(kip1) cyclin-dependent kinase (CDK) inhibitor, which is a requisite for G1 to S phase cell cycle progression. IFN-gamma does not interfere with the effects of HGF on either ERK activation or cyclin D1 induction; however, it prevents the downregulation of p27(kip1) CDK inhibitor that takes place in response to a combination of HGF and serum. These results indicate that the MEK-ERK signaling pathway is necessary but not sufficient for human bronchial epithelial cell proliferation, and implicate the significance of HGF and IFN-gamma in the repair processes of injured human bronchial epithelial cells.
Am J Respir Cell Mol Biol 2002 Feb
PMID:Interferon-gamma inhibits hepatocyte growth factor-stimulated cell proliferation of human bronchial epithelial cells: upregulation of p27(kip1) cyclin-dependent kinase inhibitor. 1180 75

Proliferation and migration of vascular smooth muscle cells (VSMCs) are believed to contribute significantly to intimal thickening in atheroscleosis, restenosis, and venous bypass graft disease. Estrogen inhibits proliferation and migration of VSMCs. However, antiproliferative mechanisms of estrogen were not well elucidated yet. In this study, we investigated the antiproliferative effect of estrogen to determine whether the transduction signals and protooncogenes were affected in rat aortic smooth muscle cells (RASMCs). Estrogen inhibited the proliferative response stimulated by 5% fetal bovine serum (FBS) dose-dependently in RASMCs (IC50: 40 nM). In 0.5% serum-treated RASMCs, estrogen dramatically inhibited the activity of extracellular signal-regulated kinases (ERK) followed by inhibition of MEK1,2 activity in dose-dependent manner without affecting the other mitogen-activating protein kinases (MAPKs), c-jun N-terminal kinases (JNK) and p38. Induction of Elk-1 mRNA was significantly reduced dose-dependently up to 100 nM of estrogen. These results indicate that the antiproliferative effects of estrogen in RASMCs involved ERK inhibition followed by the inactivation of MEK1,2 and downregulation of Elk-1 expression.
J Steroid Biochem Mol Biol 2002 Jan
PMID:Inhibition of MEK1,2/ERK mitogenic pathway by estrogen with antiproliferative properties in rat aortic smooth muscle cells. 1186 67

RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) induces differentiation of human breast cancer cells. Previous studies ruled out transforming growth factor-beta and c-jun N-terminal kinase involvement in VES-induced differentiation but implicated extracellular signal-regulated kinases (ERKs). Here we show that dominant-negative mutants of either mitogen-activated protein kinase kinase (MEK) 1 or ERK1 blocked VES-induced differentiation of MDA-MB-435 cells, as measured by induction of cytokeratin 18 and p21 (Waf1/Cip1) proteins. Blockage of c-jun protein expression using c-jun antisense oligonucleotides or expression of an inducible dominant-negative c-jun mutant protein inhibited VES-induced differentiation. Elevated expression of wild-type c-jun alone was sufficient to induce cellular differentiation. A role for p21 (Waf1/Cip1) is implicated, in that p21 antisense oligomers blocked VES-induced differentiation. In summary, MEK1, ERK1, the transcription factor c-jun, and the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1) play a part in VES-induced differentiation of human MDA-MB-435 breast cancer cells.
Mol Carcinog 2002 Apr
PMID:Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells. 1193 76

We showed previously that epithelial growth factor (EGF) receptor (EGFR) signaling is triggered by metallic compounds associated with ambient air particles. Specifically, we demonstrated that As, Zn, and V activated the EGFR tyrosine kinase and the downstream kinases MEK1/2 and ERK1/2. In this study, we examined the role of Ras in EGFR signaling and the nuclear factor-kappaB (NF-kappaB) activation pathway and the possible interaction between these two signaling pathways in a human airway epithelial cell line (BEAS-2B) exposed to As, V, or Zn ions. Each metal significantly increased Ras activity, and this effect was inhibited by the EGFR tyrosine kinase activity inhibitor PD-153035. Adenoviral-mediated overexpression of a dominant-negative mutant form of Ras(N17) significantly blocked MEK1/2 or ERK1/2 phosphorylation in As-, Zn-, or V-exposed BEAS-2B cells but caused little inhibition of V-, Zn- or EGF-induced EGFR tyrosine phosphorylation. This confirmed Ras as an important intermediate effector in EGFR signaling. Interestingly, V, but not As, Zn, or EGF, induced IkappaBalpha serine phosphorylation, IkappaBalpha breakdown, and NF-kappaB DNA binding. Moreover, PD-153035 and overexpression of Ras(N17) each significantly blocked V-induced IkappaBalpha breakdown and NF-kappaB activation, while inhibition of MEK activity with PD-98059 failed to do so. In summary, exposure to As, Zn, and V initiated EGFR signaling and Ras-dependent activation of MEK1/2 and ERK1/2, but only V induced Ras-dependent NF-kappaB nuclear translocation. EGFR signaling appears to cross talk with NF-kappaB signaling at the level of Ras, but additional signals appear necessary for NF-kappaB activation. Together, these data suggest that, in V-treated BEAS-2B cells, Ras-dependent signaling is essential, but not sufficient, for activation of NF-kappaB.
Am J Physiol Lung Cell Mol Physiol 2002 May
PMID:Role of Ras in metal-induced EGF receptor signaling and NF-kappaB activation in human airway epithelial cells. 1194 69

In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.
Mol Cell Biol 2002 May
PMID:Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. 1197 71


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