Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DiFi human colon carcinoma cells are stimulated by the transforming growth factor-alpha (TGF-alpha)/epidermal growth factor (EGF) receptor autocrine loop. Exposure of DiFi cells to monoclonal antibody (mAb) 225, which blocks ligand-induced activation of the EGF receptor, induces G1 arrest and subsequent cell death via apoptosis. We investigated the signal pathways by which basic fibroblast growth factor (bFGF) and insulin-like growth factor-1 (IGF-1) modulate mAb 225-induced G1 arrest and apoptosis in DiFi cells. Both bFGF and IGF-1 activated the mitogen-activated protein kinase (MAPK) kinase (MEK) pathway in DiFi cells. Additionally, IGF-1 activated the phosphoinositide 3-kinase (PI-3K)/Akt pathway. Both bFGF and IGF-1 inhibited mAb 225-induced apoptosis; however, bFGF provided sustained protection against apoptosis, while the protection by IGF-1 was only temporary. Also, bFGF reversed the mAb 225-induced increase in the p27(Kip1) level, inhibition of cyclin-dependent kinase-2 (CDK-2) activity, dephosphorylation of the retinoblastoma (Rb) protein and the resultant G1 arrest of the cells. In contrast, IGF-1 did not reverse such effects by mAb 225. The prevention of mAb 225-induced G1 arrest and apoptosis in DiFi cells by bFGF was sensitive to the MEK/MAPK inhibitor PD98059 but not to the PI-3K inhibitor LY294002. In contrast, inhibition of apoptosis by IGF-1 in DiFi cells was sensitive only to LY294002 and not to PD98059. These results further our understanding of how mAb 225 induces apoptosis in DiFi cells.
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PMID:Fibroblast growth factor and insulin-like growth factor differentially modulate the apoptosis and G1 arrest induced by anti-epidermal growth factor receptor monoclonal antibody. 1131 39

This paper describes the establishment of an antiestrogen-resistant MCF7 breast cancer cell subline (FASMCF) by continuous culture of the estrogen-responsive parental line in steroid-depleted, ICI 182,780 (Faslodex; 10(-7) M)-supplemented medium. After a 3-month period of growth suppression, cells began to proliferate in ICI 182,780 at rates similar to those of untreated wild-type cells. Immunocytochemistry showed these cells to have reduced estrogen receptor and an absence of progesterone receptor proteins. RT-PCR and transient transfection studies with estrogen response element-reporter constructs confirmed that ICI 182,780-suppressed estrogen response element-mediated signaling. FASMCF cells show increased dependence upon epidermal growth factor receptor (EgfR)/mitogen-activated protein kinase (MAPK)-mediated signaling. Thus, EgfR protein and messenger RNA, growth responses to transforming growth factor-alpha, and extracellular signal-regulated kinase 1/2 MAPK activation levels are all increased. Unlike wild-type cells, FASMCF cells are highly sensitive to growth inhibition by an EgfR-specific tyrosine-kinase inhibitor (TKI), ZD1839 (Iressa), and an inhibitor of the activation of MEK1 (MAPKK), PD098059. Short-term ( approximately 3 weeks) withdrawal of cells from antiestrogen had no effect on growth or phenotype, whereas longer withdrawal (>10 weeks) appeared to partially reverse the cellular phenotype with increasing estrogen receptor and decreasing EgfR levels. In subsequent studies FASMCF cells were maintained in TKI, where their growth was again suppressed and secondary TKI resistance failed to develop within the 3-month period in which initial ICI 182,780 resistance arose. Furthermore, wild-type cells similarly maintained in combination ICI 182,780 and TKI treatment conditions remained growth arrested (>6 months), with notable cell loss through both reduced rates of cellular proliferation and increased cell death.
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PMID:Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). 1141 96

Phosphorylation of extracellular signal-regulated kinases (ERK1/ERK2) has been implicated in cell proliferation of mammalian cells. In the present study, we investigated the role of docosahexaenoic acid (DHA) in the modulation of ERK1/ERK2 phosphorylation, stimulated either with phorbol 12-myristate 13-acetate (PMA) or transforming growth factor-alpha (TGFalpha) in NIH/3T3 cells. We observed that both PMA and TGFalpha induced ERK1/ERK2 phosphorylation within 5 min of stimulation. PMA acts upstream of MEK and via activation of protein kinase C (PKC), as GF109203X, a potent PKC inhibitor, and U0126, a MEK inhibitor, abolished its actions on ERK1/ERK2 phosphorylation. TGFalpha did not act via PKC because GF109203X failed to curtail the degree of ERK1/ERK2 phosphorylation in these cells. DHA alone failed to induce the phosphorylation of these mitogen-activated protein (MAP) kinases; however, this fatty acid significantly curtailed the PMA- but not TGFalpha-induced MAP kinase enzyme activity and phosphorylation in NIH/3T3 cells. Furthermore, we observed that DHA significantly inhibited PMA-induced translocation of two PKC isoforms, PKC alpha and PKC epsilon, from cytosol to plasma membrane. Interestingly, DHA failed to inhibit the PMA-induced translocation PKC delta isoform in these cells. Furthermore, DHA decreased PMA-induced proliferation of NIH/3T3 cells. In this study, we show for the first time that DHA inhibits MAP kinase ERK1/ERK2) activation and proliferation of NIH/3T3 cells via its inhibitory action on PKC alpha and epsilon isoforms.
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PMID:Docosahexaenoic acid modulates phorbol ester-induced activation of extracellular signal-regulated kinases 1 and 2 in NIH/3T3 cells. 1159 32

The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 ("Iressa") on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-alpha stimulated growth was completely inhibited by concentrations of ZD 1839 > or =0.3 microM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-alpha stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-alpha was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-alpha, EGF and amphiregulin mRNAs were detected by RT-PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(-1)day(-1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit.
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PMID:Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 ("Iressa"). 1187 15

We investigated the potential of genistein, the primary isoflavone of soy, to protect against breast and prostate cancers in animal models. For mammary cancer studies, Sprague-Dawley rats were fed AIN-76A diet plus minus 250 mg genistein/kg diet. Dimethylbenz[a]anthracene was administered by gavage at d 50 postpartum to induce mammary tumors. Mammary cancer chemoprevention was demonstrated after prepubertal and combined prepubertal and adult genistein treatments but not after prenatal- or adult-only treatments, demonstrating that the timing of exposure to genistein is important for mammary cancer chemoprevention. The cellular mechanism of action was found to be mammary gland and cell differentiation, as shown by whole-mount analysis and beta-casein expression. An imprinting effect was shown for epidermal growth factor receptor expression in mammary terminal end buds. For prostate cancer studies, we used two models. The first was a chemically (N-methylnitrosourea) induced prostate cancer rat model. Genistein in the diet inhibited the development of invasive adenocarcinomas in a dose-dependent manner. The second model was a transgenic mouse model that resulted in spontaneously developing adenocarcinoma tumor of the prostate. Genistein in the diet reduced the incidence of poorly differentiated prostatic adenocarcinomas in a dose-dependent manner and down-regulated androgen receptor, estrogen receptor-alpha, progesterone receptor, epidermal growth factor receptor, insulin-like growth factor-I, and extracellular signal-regulated kinase-1 but not estrogen receptor-beta and transforming growth factor-alpha mRNA expressions. We conclude that dietary genistein protects against mammary and prostate cancers by regulating specific sex steroid receptors and growth factor signaling pathways.
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PMID:Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. 1188 May 92

Laminin-5 is an extracellular matrix protein that plays a key role in cell migration and tumor invasion. Cox-2 is an induced isoform of cyclooxygenases that plays an important role in carcinogenesis, suppression of apoptosis, angiogenesis, and metastasis of colon cancer. We report frequent co-expression of cox-2 and laminin-5 at the invasive front of early-stage lung adenocarcinomas. We investigated the expression of cox-2 and laminin-5 immunohistochemically in 102 cases of small-sized lung adenocarcinoma (maximum dimension, 2 cm or less). Cox-2 and laminin-5 were expressed in 97 (95.1%) and 82 (80.4%) cases, respectively. Both were preferentially localized in cancer cells at the cancer-stroma interface, although cox-2 tended to show a diffuse staining pattern in some cases. A comparison of their staining patterns revealed a striking similarity in their distribution in 24 cases, and a partial overlap between their localization in another 20 cases. Moreover, an overall correlation was found between the expression levels of cox-2 and laminin-5 (P = 0.018). To gain insight into the mechanisms that regulate the expression of these proteins, we additionally studied their expression in 58 cases of stage I lung adenocarcinoma, in which p53 status was determined by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism analysis, and direct sequencing. The results showed that tumors with mutant p53 tended to express more cox-2 than those with wild-type p53 (P = 0.080). Also, tumors that overexpressed p53 had higher levels of cox-2 and laminin-5 than those without p53 overexpression (P = 0.032 and 0.047, respectively). Further immunohistochemical analysis showed that tumors that overexpressed both epidermal growth factor receptor (EGFR) and erbB-2 had higher levels of cox-2 and laminin-5 than those without concomitant overexpression of these proteins (P = 0.014 and P = 0.018, respectively). To see whether EGFR signaling is involved in cox-2 and laminin-5 expression, we further conducted in vitro analyses using six lung adenocarcinoma cell lines (A549, HLC-1, ABC-1, LC-2/ad, VMRC-LCD, and L27). Western blot analyses showed that cox-2 mRNA levels, and to a lesser extent laminin-5 gamma2 mRNA levels, correlated with the expression levels of erbB-2 and the phosphorylated form of MAPK/ERK-1/2 protein. The addition of transforming growth factor-alpha increased both cox-2 and laminin-5 gamma2 mRNA levels in A549, ABC-1, and L27 with different kinetics; the induction of cox-2 occurred earlier than that of laminin-5 gamma2. Finally, the migration of ABC-1 cells was inhibited by MAP kinase kinase inhibitor PD98059 and a selective cox-2 inhibitor NS-398. In contrast, the migration of A549 cells was inhibited by PD98059, but much less effectively by NS-398. These results suggest that co-stimulatory mechanisms may exist that increase the expression of cox-2 and laminin-5 at the invasive front of lung adenocarcinomas and that EGFR signaling could be one of the mechanisms. Further investigations are warranted concerning the role of cox-2 and laminin-5 in cancer cell invasion and the significance of p53 and EGFR signaling in the regulation of cox-2 and laminin-5 expression.
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PMID:Frequent co-localization of Cox-2 and laminin-5 gamma2 chain at the invasive front of early-stage lung adenocarcinomas. 1189 Dec 9

In spite of lower receptor affinity, epiregulin exhibits a stronger stimulation of DNA synthesis than epidermal growth factor (EGF) in rat hepatocytes. To determine the mechanism of stimulation, we examined the activities of epiregulin on growth stimulation, signal transduction, and mRNA induction of hepatotrophic factors in primary cultures of rat hepatocytes. Epiregulin stimulated hepatocyte proliferation as efficiently as hepatotrophic factors, including heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-alpha). Epiregulin induced a more prolonged activation of EGF receptor (EGFR) and p42/44 mitogen-activated protein kinase (MAPK) than EGF. Furthermore, epiregulin up-regulated the mRNAs of TGF-alpha and HB-EGF, and in turn, these growth factors enhanced the expression of epiregulin mRNA. In vivo, increased production of epiregulin was noted in extracts of the remnant liver obtained 24 h after partial hepatectomy, and EGFR phosphorylation by these extracts was partially inhibited by anti-epiregulin antibody. Our results showed a more potent hepatocyte proliferative activity for epiregulin compared with EGF in vitro, which depends on prolonged activation of EGFR and p42/44 MAPK. Our findings suggest that epiregulin may play significant roles in liver regeneration following partial hepatectomy in cooperation with other growth factors.
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PMID:Mechanism of growth promoting activity of epiregulin in primary cultures of rat hepatocytes. 1214 64

IGF-binding protein-3 (IGFBP-3) potentiates IGF-I action in the non-transformed mammary epithelial cell line, MAC-T, via a mechanism that is independent of its ability to bind IGF-I. The goal of the present study was to determine if IGFBP-3 might enhance IGF action by influencing intracellular signaling events downstream of the IGF receptor. IGF-I stimulated a time-dependent activation of Akt in which phosphorylation of Ser(473) was detectable by 1 min and maximal at 15 min. In contrast, no activation of extracellular signal-regulated kinase (ERK)1/2 by IGF-I was observed although basal phosphorylation was readily detectable. In MAC-T cells constitutively expressing IGFBP-3 (+BP3), phosphorylation of Akt following stimulation with IGF-I was enhanced relative to mock-transfected cells (Mock). The enhancement was detectable within 1 min of IGF-I treatment and persisted for up to 10 h. The increased phosphorylation observed by Western blotting corresponded to a 1.7-fold increase in Akt kinase activity. The enhanced Akt response was elicited by factors that activate the IGF receptor but exhibit reduced affinity for IGFBP-3, such as Long R(3)IGF-I, B chain IGF-I and insulin. In contrast, [Leu(60)]IGF-I, which binds IGFBP-3 but has reduced affinity for the IGF receptor, failed to induce comparable activation, suggesting that an association between IGF-I and IGFBP-3 is not required for the effect. The enhanced Akt activation could not be mimicked by addition of exogenous IGFBP-3. Akt phosphorylation was also enhanced by transforming growth factor-alpha in +BP3 cells, indicating that the effect was not specific to IGF-I. Similar to Akt, phosphorylation of p70S6 kinase (p70(S6K)) by IGF-I was also enhanced in +BP3 cells relative to Mock cells at both 15 min and 10 h. However, this was largely an effect of lower basal activation of p70(S6K) in +BP3 cells. These data indicate that endogenous IGFBP-3 potentiates IGF action in MAC-T cells by enhancing signaling via the phosphatidylinositol 3-kinase pathway at a point that is downstream of IGF receptor activation. Further studies will delineate specific mechanisms by which IGFBP-3 may influence intracellular events that regulate growth in mammary epithelial cells.
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PMID:Constitutive expression of IGF-binding protein-3 by mammary epithelial cells alters signaling through Akt and p70S6 kinase. 1220 Feb 36

The effects of the ERK pathway on electrogenic transepithelial Na(+) absorption by renal collecting duct cells were determined. Approximately 90% of the unstimulated short-circuit current (15 +/- 1 microA/cm(2), n = 10) across conditionally immortalized murine collecting duct epithelial cells (mCT1) is amiloride sensitive and is likely mediated by apical epithelial Na(+) channels. Chronic exposure (24 h) of the epithelial monolayers to either EGF (50 ng/ml) or transforming growth factor-alpha (TGF-alpha; 20 ng/ml) reduced amiloride-sensitive short-circuit current by >60%. The inhibitory effect of EGF on Na(+) absorption was not due to inhibition of basolateral Na(+)-K(+)-ATPase, because the pump current elicited by permeabilization of apical membrane with nystatin was not reduced by EGF. Chronic exposure of the mCT1 cells to EGF (20 ng/ml, 24 h) elicited a 70-85% decrease in epithelial Na(+) channel subunit mRNA levels. Exposure of mCT1 cells to either EGF (20 ng/ml) or PMA (150 nM) induced rapid phosphorylation of p42/p44 (ERK1/2) and pretreatment of the monolayers with PD-98059 (an ERK kinase inhibitor; 30 microM) prevented phosphorylation of p42/p44. Similarly, pretreatment of mCT1 monolayers with PD-98059 prevented the EGF- and PMA-induced inhibition of amiloride-sensitive Na(+) absorption. The results of these studies demonstrate that amiloride-sensitive Na(+) absorption by renal collecting duct cells is regulated by the ERK pathway. This pathway may play a role in alterations in ion transport that occur in polycystic kidney disease.
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PMID:Epidermal growth factor inhibits amiloride-sensitive sodium absorption in renal collecting duct cells. 1238 7

Tumor necrosis factor-alpha converting enzyme (TACE) is a prototype member of the adamalysin family of transmembrane metalloproteases that effects ectodomain cleavage and release of many transmembrane proteins, including transforming growth factor-alpha. Growth factors that act through tyrosine kinase receptors, as well as other stimuli, induce shedding through activation of the Erk mitogen-activated protein (MAP) kinase pathway without the need of new protein synthesis. How MAP kinase regulates shedding by TACE is not known. We now report that the cytoplasmic domain of TACE is phosphorylated in response to growth factor stimulation. We also identified a naturally expressed smaller polypeptide corresponding to most of the cytoplasmic domain of TACE. This protein, which we named SPRACT, is derived through alternative translation of the TACE-coding sequence and is, similarly to TACE, phosphorylated in response to growth factor and phorbol 12-myristate 13-acetate stimulation. Phosphoamino acid analysis revealed that growth factor-induced phosphorylation of TACE occurs only on serine and not on threonine or tyrosine. Tryptic mapping experiments coupled with site-directed mutagenesis identified Ser(819) as the major target of growth factor-induced phosphorylation, whereas Ser(791) undergoes dephosphorylation in response to growth factor stimulation. The phosphorylation of Ser(819), but not the dephosphorylation of Ser(791), depends on activation of the Erk MAP kinase pathway. Increased SPRACT expression or mutation of the TACE cytoplasmic domain to inactivate growth factor-induced phosphorylation did not detectably affect growth factor-induced shedding of transmembrane transforming growth factor-alpha by TACE. The roles of SPRACT and the cytoplasmic phosphorylation of TACE remain to be defined.
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PMID:Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. 1262 Oct 58


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