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

In this study, we show that the ETS transcription factor ER81 directly binds to and activates the promoter of the matrix metalloproteinase gene, MMP-1. Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription. The activation of ER81 by HER2/Neu is mediated by MAP kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further diminished by abolishment of phosphorylation at two non-MAP kinase sites. Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.
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PMID:HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. 1159 30

The purpose of this study was to investigate the frequency of expression of the erbB/HER family of growth factor receptors, their ligand heregulin, and the two different signaling pathways p38 and mitogen-activated protein kinase (MAPK), as well as the status of HER-2 phosphorylation in tumor specimens from patients with primary breast cancer. The level of expression of these proteins was measured by quantitative immunohistochemistry combined with microscope-based image analysis in paraffin-embedded breast cancer tissue from 35 patients. The frequency of expression was: EGFR (51%), HER-2 (54%), P-HER-2 (48%), HER-3 (48%), HER-4 (57%), heregulin (48%), p38 (17%), MAPK (48%). There was evidence of associations among the coexpression of heregulin, EGFR, HER-2, and HER-3. Also, there was evidence of a positive association between P-MAPK and HER-4. HER-3 was expressed at high levels in patients younger than 50 years of age. There was a trend for expression of higher levels of HER-4 in tumors larger than 2 cm. The expression of EGFR, HER-2, heregulin, p38 and MAPK was independent of age, tumor size, number of lymph nodes involved or hormone receptor status. The HER family of growth factor receptors appear to be regulated independently in invasive breast cancer. Assessing the expression of multiple tumor markers by quantitative immuno-histochemistry is feasible. Further research is needed to determine the prognostic and predictive roles of the various associations between HER receptors, their ligands and signal transduction molecules in patients with early-stage breast cancer.
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PMID:Expression of erbB/HER receptors, heregulin and P38 in primary breast cancer using quantitative immunohistochemistry. 1169 42

The growth factor receptor-bound protein-2 (GRB2) is essential for multiple cellular functions. Inhibition of GRB2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. GRB2 is most well known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of RAS and its downstream kinases, ERK1,2. We recently reported that GRB2 does not link the HER2 tyrosine kinase to the activation of ERK1,2 but to another kinase, AKT. So, different tyrosine kinases may converge on GRB2 for signaling; however, they may not always use GRB2 to effect the same downstream kinases for cellular functions. It is likely that GRB2 will be found to regulate many more kinases because it plays such a pivotal role in signal transduction.
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PMID:GRB2: a pivotal protein in signal transduction. 1170 5

Recognition of altered self-antigens in tumor cells by lymphocytes forms the basis for antitumor immune responses. The effector cells in most experimental tumor systems are CD8(+) T cells that recognize MHC class I binding peptides derived from molecules with altered expression in tumor cells. Although the need for CD4(+) helper T cells in regulating CD8(+) T cells has been documented, their target epitopes and functional impact in antitumor responses remain unclear. We examined whether broadly expressed wild-type molecules in murine tumor cells eliciting humoral immunity contributed to the generation of CD8(+) T cells and protective antitumor immune responses to unrelated tumor-specific antigens [mutated ERK2 (mERK2) and c-erbB2/HER/neu (HER2)]. The immunogenic wild-type molecules, presumably dependent on recognition by CD4(+) helper T cells, were defined by serological analysis of recombinant cDNA expression libraries (SEREX) using tumor-derived lambda phage libraries screened with IgG antibodies of hosts bearing transplanted 3-methylchoranthrene-induced tumors. Coimmunization of mice with plasmids encoding SEREX-defined murine wild-type molecules and mERK2 or HER2 led to a profound increase in CD8(+) T cells specific for mERK2 or HER2 peptides. This heightened response depended on CD4(+) T cells and copresentation of SEREX-defined molecules and CD8(+) T cell epitopes. In tumor protection assays, immunization with SEREX-defined wild-type molecules and mERK2 resulted in an inhibition of pulmonary metastasis, which was not achieved by immunization with mERK2 alone.
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PMID:Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity. 1172 51

Clinical responses to the HER1 (EGF receptor) inhibitors and HER2/neu/ErbB2 inhibitors correlate with high levels of receptor expression. However, a significant subset of patients with high receptor levels appear to be refractory to treatment. We have observed similar results in the 60 cell lines of the NCI Anti-Cancer Drug Screen using a panel of 11 selective HER1 inhibitors. As expected, low HER1-expressing cell lines were insensitive to HER1 inhibitors. In cell lines with high HER1 expression, low concentrations of HER1 inhibitors potently inhibit both HER1 phosphorylation and the mitogen-activated protein kinase (MAPK) pathway. However, this inhibition did not always correlate with cellular arrest. High HER1-expressing cell lines can be subdivided into two groups based on their sensitivity to HER1 inhibitors. In the sensitive group, receptor and growth inhibition was concordant and occurred at sub-micromolar concentrations of HER1 inhibitors. In the insensitive group, receptor inhibition occurred at a low concentration (< 1 microM) but concentrations that were ten times or higher were required for growth inhibition. Also, neither induction of p21 and cyclin D1 nor p53 status could explain the difference between sensitive and insensitive cells. Although EGF activated the MAPK pathway in all cell lines, only drug-sensitive cell lines responded to EGF (accelerated entry from G1 to S) and to HER1 inhibitors (G1 arrest) by changes in cell cycling. Furthermore, an EGF-dependent immortalized mammary epithelial cell line was extremely sensitive to a panel of HER1 inhibitors. We infer that independence from mitogen-mediated signaling confers insensitivity to HER1 inhibitors in a large subset of cancer cell lines.
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PMID:Differential sensitivity of cancer cells to inhibitors of the epidermal growth factor receptor family. 1179 Nov 82

Epidermal growth factor receptor (EGFR) and HER-2/ErbB2 are members of the Erb family of signaling receptors. ErbB2 is overexpressed in many different cancers and has been linked to enhanced malignancy of tumors. We have examined the cellular translocation of Raf-1 during EGF-dependent signal transduction in two breast tumor cell lines, BT20 and SKBR3. Treatment of BT-20 breast cancer cells, which express EGFR, with EGF resulted in rapid (5 minutes) accumulation of EGFR and Raf-1 into plasma membrane-associated endocytotic vesicles. However, at later time points (30 minutes) only EGFR was endocytosed and Raf-1 dissociated from the plasma membrane and was found in the cytosol. In SKBR3 breast cancer cells, which express high levels of EGFR and ErbB2, treatment with EGF also resulted in rapid accumulation of EGFR and Raf-1 into endocytotic vesicles, but EGFR endocytosis was inhibited and Raf-1 remained associated with the plasma membrane for a prolonged period. The role of ErbB2 in the retention of Raf-1 at the plasma membrane was confirmed in BT-20 cells transfected with ErbB2. BT-20 cells expressing ErbB2 and treated with EGF retained Raf-1 at the plasma membrane for prolonged periods, whereas Raf-1 rapidly dissociated from the plasma membrane in EGF-stimulated cells transfected with a control vector. The presence of Raf-1 at the plasma membrane correlated with activation of Raf-1 and MAP kinase. Cells that expressed ErbB2 and treated with EGF showed prolonged activation of Raf-1 and MAP kinase compared with cells that expressed low levels of ErbB2. These results suggest that expression of ErbB2 promoted retention of Raf-1 in the plasma membrane, resulting in prolonged activation of the MAP kinase cascade, which may contribute to enhanced malignancy in ErbB2-expressing cancers.
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PMID:EGFR and ErbB2 differentially regulate Raf-1 translocation and activation. 1179 27

It has been proposed that binding of ligand to the estrogen receptor (ER) releases its association with transcriptional corepressors, allowing the ER to recruit coactivators, which possess histone acetylase activity, and induce transcription of gene promoters containing estrogen response elements. It has also been proposed that the antiestrogen tamoxifen recruits transcriptional corepressors to the AF-2 region of the hormone-binding domain of the ER, thus blocking ER-mediated transcription. The ER cross-talks with a number of mitogenic signaling pathways and second messengers, like the epidermal growth factor receptor, the insulin-like growth factor-I receptor, mitogen-activated protein (MAP) kinase, phosphatidylinositol-3 kinase/Akt, dopamine, and cyclic AMP. Some of these molecules may: (a) support ligand-independent ER transcription; (b) increase the association of ER with coactivators of transcription; and/or (c) reduce the antiestrogen-induced association of ER with corepressors. These events either alone or in combination may result in hormone independence and/or antiestrogen resistance. We have examined whether signaling by HER2/neu (erbB-2) receptor tyrosine kinase, which can induce antiestrogen resistance, can also disrupt the tamoxifen-induced interaction of ER with transcriptional corepressors. Notably, tamoxifen-induced association of ER with the transcriptional corepressors N-CoR or SMRT was reduced in HER2-overexpressing breast tumor cells but not in cells with low HER2 levels. Small molecule inhibitors of the HER2 kinase or MAP extracellular signal-regulated kinase 1/2 or dominant-negative MAP extracellular signal-regulated kinase 1/2 constructs restored the inhibitory effect of tamoxifen on both ER-mediated transcription and tumor cell proliferation. Treatment with both tamoxifen and the small molecule HER1/2 kinase inhibitor AG1478 reduced mitogen-activated protein kinase activity and markedly reduced growth of established MCF-7/HER2 xenografts in athymic nude mice. Similar results have been obtained with ZD1839 ("Iressa"), an epidermal growth factor receptor (HER1) tyrosine kinase inhibitor. Taken together, these data suggest that exogenous inhibitors of the HER-signaling network and other mitogenic pathways can abrogate or delay the emergence of antiestrogen resistance, thus providing an evaluable therapeutic strategy in human breast carcinoma.
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PMID:Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. 1191 37

Activation of mitogen-activated protein kinase (Erk/MAPK) is a critical signal transduction event for estrogen (E(2))-mediated cell proliferation. Recent studies from our group and others have shown that persistent activation of Erk plays a major role in cell migration and tumor progression. The signaling mechanism(s) responsible for persistent Erk activation are not fully characterized, however. In this study, we have shown that E(2) induces a slow but persistent activation of Erk in MCF-7 breast carcinoma cells. The E(2)-induced Erk activation is dependent on new protein synthesis, suggesting that E(2)-induced growth factors play a major role in Erk activation. When MCF-7 cells were treated with E(2) in the presence of an anti-HER-2 monoclonal antibody (herceptin), 60-70% of E(2)-induced Erk activation is blocked. In addition, when untreated MCF-7 cells were exposed to conditioned medium from E(2)-treated cells, Erk activity was significantly enhanced. Furthermore Erk activity was blocked by an antibody against HER-2 or by heregulin (HRG) depletion from the conditioned medium through immunoprecipitation. In contrast, epidermal growth factor receptor (Ab528) antibody only blocked 10-20% of E(2)-induced Erk activation, suggesting that E(2)-induced Erk activation is predominantly mediated through the secretion of HRG and activation of HER-2 by an autoctine/paracrine mechanism. Inhibition of PKC-delta-mediated signaling by a dominant negative mutant or the relatively specific PKC-delta inhibitor rottlerin blocked most of the E(2)-induced Erk activation but had no effect on TGF alpha-induced Erk activation. By contrast inhibition of Ras, by inhibition of farnesyl transferase (Ftase-1) or dominant negative (N17)-Ras, significantly inhibited both E(2)- and TGF alpha-induced Erk activation. This evaluation of downstream signaling revealed that E(2)-induced Erk activation is mediated by a HRG/HER-2/PKC-delta/Ras pathway that could be crucial for E(2)-dependent growth-promoting effects in early stages of tumor progression.
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PMID:Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. 1196 Sep 91

Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.
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PMID:Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. 1197 39

Overexpression of the HER2/Neu receptor is correlated to a poor prognosis in tumor patients and leads to stimulation of mitogen-activated protein kinase (MAPK) signaling pathways, which in turn activate transcription factors, such as the ETS protein ER81. Here, we have analyzed whether, on the other hand, ER81 may regulate the Her2/neu gene. Indeed, ER81, together with its co-activators, p300 and CBP, activates the Her2/neu promoter, and this activation is enhanced upon stimulation of MAPK pathways as well as by oncogenic HER2/Neu protein. Furthermore, ER81 interacts with one ETS binding site in the Her2/neu promoter, whose mutation decreases ER81-mediated transcription. Activation of the Her2/neu promoter is also diminished upon mutation of MAPK-dependent phosphorylation sites in ER81 or upon deletion of ER81 transactivation domains. In addition, the ER81 DNA-binding domain on its own functions as a dominant-negative molecule, effectively repressing any stimulation of the Her2/neu promoter. Altogether, our results show that ER81 is a component of a positive regulatory feedback loop, in which the HER2/Neu protein activates ER81, as well as p300/CBP via MAPKs causing the upregulation of the Her2/neu gene.
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PMID:Regulation of Her2/neu promoter activity by the ETS transcription factor, ER81. 1211 28


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