Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myxoid liposarcomas (MLS) carry a t(12;16) or, more rarely, a t(12;22) resulting in fusion of the transcription factor gene CHOP on chromosome 12 with TLS/FUS on chromosome 16 or EWS on chromosome 22. The chimeric TLS-CHOP or EWS-CHOP proteins most probably function as abnormal transcription factors, causing transcriptional de-regulation of several target genes and relaxation of functions critical for growth and differentiation control. A PCR-based subtractive hybridization technique was used to identify genes that are differentially expressed in TLS-CHOP-carrying MLS but not in normal fat tissue. Six myxoid-liposarcoma-associated transcripts, MLAT, were isolated. The genes identified as MLAT can be divided into 2 groups. MLAT1, 2 and 6 show high similarity to glia-derived nexin, neuronatin and the RET oncogene, respectively, all normally involved in development of tissues of neural origin. MLAT3 to MLAT5 represent new genes.
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PMID:Identification of genes differentially expressed in TLS-CHOP carrying myxoid liposarcomas. 1044 3

We demonstrate here that p38 mitogen-activated protein (MAP) kinase is activated in response to cellular stimulation by human GH (hGH) in Chinese hamster ovary cells stably transfected with GH receptor cDNA. This activation requires the proline-rich box 1 region of the GH receptor required for JAK2 association and is prevented by pretreatment of cells with the JAK2-specific inhibitor AG490. ATF-2 is both phosphorylated and transcriptionally activated by hGH, and its transcriptional activation also requires the proline-rich box 1 region of the GH receptor. Expression of wild type JAK2 can further enhance hGH-induced ATF-2-, CHOP-, and Elk-1-mediated transcriptional activation, whereas pretreatment with AG490 is inhibitory. Use of either specific pharmacological inhibitors or transient transfection of cells with p38alpha MAP kinase cDNA or a dominant negative variant demonstrated that hGH-stimulated transcriptional activation of ATF-2 and CHOP, but not Elk-1, is regulated by p38 MAP kinase. Both the p38 MAP kinase and p44/42 MAP kinase are critical for hGH-stimulated mitogenesis, whereas only p38 MAP kinase is required for hGH-induced actin cytoskeletal re-organization. p38 MAP kinase is therefore an important regulator in coordinating the pleiotropic effects of GH.
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PMID:Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. 1063 15

Glioblastoma multiforme (GBM) is the most common primary tumor occurring in the central nervous system of adults. Although progress has been made in clinical management of this tumor, little is known about the molecular defects underlying the initiation and progression of GBM. To address these issues, we have characterized five cases of GBM using cytogenetics, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and direct sequencing. All of these tumors were observed to have clonal chromosome aberrations. Complicated chromosome translocations including der(18)t(2;4;12;18), der(X)t(X;10)(q27.1;p12.1) and der(10)t(10;15)(p11.23;q11.2), and der(1) (:1p31-->1q44::7q11. 3-->7qter) were seen in three tumors. Loss of the CDKN2 gene was noted in four tumors. A gain of copy number of the Cathepsin L gene was seen in two tumors. Amplification of the CDK4, MDM2, and GLI/CHOP genes was noted in two tumors, and amplification of the PDGFR gene was detected in one tumor. Mutation of exon 5 of the TP53 gene was found in three tumors. No mutation of the BCL10 gene was detected in five cases of GBM analyzed, although deletion of chromosome 1p was seen in two tumors. These results provide information for further investigation of GBM.
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PMID:Molecular and cytogenetic analysis of glioblastoma multiforme. 1110 17

The human GH (hGH) antagonist B2036 combines a single amino acid substitution impairing receptor binding site 2 (G120K) with eight additional amino acid substitutions that improve binding site 1 affinity. B2036 does not bind, activate, or antagonize the human PRL receptor and therefore is suitable to determine cellular effects mediated specifically through the hGH receptor. We have used this hGH receptor specific antagonist in MCF-7 cells stably transfected with either the hGH gene (MCF-hGH) or a translation deficient hGH gene (MCF-MUT) to determine whether the effects of autocrine hGH on mammary carcinoma cell behavior are mediated via the hGH receptor. Enhanced JAK2 tyrosine phosphorylation observed in MCF-hGH cells compared with MCF-MUT cells is abrogated by B2036 as is the autocrine hGH stimulated increase in total cell number and DNA synthesis. Interestingly, autocrine hGH functions as a potent inhibitor of apoptosis induced by serum withdrawal compared with exogenously added hGH, and the protection against apoptosis afforded by autocrine hGH is abrogated by B2036. B2036 also inhibited autocrine hGH stimulated transcriptional activation mediated by either STAT5, CHOP (p38 MAP kinase specific) or Elk-1 (p44/42 MAP kinase specific). Finally, B2036 inhibited the autocrine hGH-dependent enhancement of the rate of mammary carcinoma cell spreading on a collagen matrix. Thus, the effects of autocrine hGH on human mammary carcinoma cell behavior are mediated via the hGH receptor.
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PMID:The effects of autocrine human growth hormone (hGH) on human mammary carcinoma cell behavior are mediated via the hGH receptor. 1115 49

Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-RP). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.
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PMID:Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells. 1157 18

Heregulin-beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 (HER3) and HER4, is a regulatory polypeptide having distinct biological effects, such as growth stimulation, differentiation, invasiveness, and migration in mammary epithelial cells. The mechanism underlying the diverse functions of HRG is not well established but is believed to depend on induced changes in the expression of specific cellular gene products, their modification, or both. Here, we identified the basic leucine zipper transcription factor, the growth-arrest and DNA-damage 153 (GADD153)/CCAAT-enhancer binding protein (C/EBP) homologous protein (CHOP) as one of the HRG-inducible genes. We demonstrated that HRG stimulation of mammary epithelial cells induces the expression of GADD153 mRNA and protein and transcription of GADD153 promoter. The transcriptional activity of the GADD153 promoter as well as transcription from the C/EBP-activating transcription factor (ATF) composite motif in the GADD153 promoter was also stimulated by HRG-inducible ATF-4 and activated HER2 but not wild-type HER2. GADD153 expression was upregulated by the lactogenic hormones insulin and progesterone and associated with differentiation of normal mammary epithelial cells. Consistent with its role as transcriptional modifier, GADD153 stimulated transcription of beta-casein promoter activity in a STAT5a-sensitive manner in mammary epithelial cells. Analysis of mouse mammary gland development revealed that GADD153 expression was predominantly restricted in the early lactating stages. Because cyclic AMP responsive element and ATF binding sites are present in a variety of growth-regulating cellular genes, these findings suggest that stimulation of GADD153 expression and its transactivating functions may constitute an important mechanism of regulation of putative genes having diverse functions during cell growth and differentiation.
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PMID:Expression and transactivating functions of the bZIP transcription factor GADD153 in mammary epithelial cells. 1208 16

After dissemination from a primary tumor, cancer cells may resume growth, leading to overt metastasis, or enter a state of protracted dormancy. However, mechanisms that determine their fate, or markers that predict it, are mostly unavailable. We previously showed that in HEp3 human head and neck carcinoma, the extracellular signal-regulated kinase (ERK)(MAPK)/p38(SAPK) activity ratio predicts whether the cells will proliferate or enter a state of dormancy in vivo. The proliferative balance of high ERK/p38 ratio was induced by high urokinase (uPA) receptor (uPAR) expression, which activated alpha5beta1-integrin and epidermal growth factor receptor. This signaling pathway was additionally enhanced by uPA binding to uPAR and fibronectin binding to alpha5beta1-integrin. We tested whether the ERK/p38 balance is predictive of in vivo behavior in other cancer cell types and whether altering the balance will shift their phenotype between proliferation and dormancy. ERK and p38 activities were determined using either phospho-specific monoclonal antibodies or a trans-reporting system where GAL4-Elk and GAL4-CHOP trans-activation of luciferase gene served as reporters for ERK and p38 activities, respectively. We show that in breast, prostate, melanoma, and fibrosarcoma cell lines, the level of active phospho-ERK and the ERK/p38 activity ratio predict for the in vivo behavior in approximately 90% of the cell lines tested. Modulation of ERK/p38 activity ratio by multiple pharmacological and genetic interventions confirms that high ERK/p38 ratio favors tumor growth, whereas high p38/ERK ratio induces tumor growth arrest (dormancy) in vivo and that ERK is negatively regulated by p38. A melanoma cell line appeared to have developed an escape mechanism to avoid the growth inhibitory effect of high p38 activity. Mechanistic analysis implicated high uPAR expression and its interaction with and activation of alpha5beta1-integrin as determinants of the in vivo growth promoting high ERK/p38 ratio in several cell lines. The small GTPase, Cdc42, was implicated in activation of p38 and growth arrest. These results suggest that even cells that originate in advanced cancers retain a degree of dependence on surface receptors and matrix for their proliferative signals in vivo and provide a therapeutic opportunity to change their phenotype from tumorigenic to dormant.
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PMID:ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). 1267 Sep 23

Here we present an unusual case of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALCL), appearing as a primary tumor of the pancreas which invaded into the adjacent duodenal wall, causing upper gastrointestinal bleeding. After complete resection of the tumor (Whipple's operation), the patient received 4 cycles of CHOP chemotherapy. Currently, 2 years after diagnosis the patient still remains lymphoma free. Primary ALCL of the pancreas is very rare and has only been reported on one previous occasion. Nevertheless, lymphoma should be considered in the differential diagnosis of pancreatic tumors and an attempt to obtain tissue diagnosis is always necessary before continuing with radical surgery, especially in young patients.
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PMID:Primary ALK positive anaplastic large cell lymphoma of the pancreas. 1269 Nov 66

Mitogen-activated protein kinases (MAPKs) mediate signaling from the cell membrane to the nucleus following their phosphorylation at conserved threonine and tyrosine residues within their activation loops. We show that protein tyrosine phosphatase epsilon (PTP epsilon) inhibits ERK1 and ERK2 kinase activity and reduces their phosphorylation; in agreement, ERK phosphorylation is increased in fibroblasts and in mammary tumor cells from mice genetically lacking PTP epsilon. PTP epsilon inhibits events downstream of ERKs, such as transcriptional activation mediated by Elk1 or by the serum response element. PTP epsilon also inhibits transcriptional activation mediated by c-Jun and C/EBP binding protein (CHOP) but not that mediated by the unrelated NFkB, attesting that it is broadly active within the MAPK family but otherwise specific. The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling. Slow induction of PTP epsilon and its lack of nuclear translocation following mitogenic stimulation suggest that PTP epsilon functions to prevent inappropriate activation and to terminate prolonged, rather than acute, activation of ERK in the cytosol.
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PMID:Protein tyrosine phosphatase epsilon inhibits signaling by mitogen-activated protein kinases. 1275 1

Mouse, chimeric, humanized and human monoclonal antibodies (MABs) are all in use for treatment of human cancer. Unconjugated antibodies have a complex mechanism of action, dependent on the nature of the target structure. Antibodies can activate the immune system (antibody-dependent cellular cytotoxicity [ADCC], complement-dependent cytotoxicity [CDC], induction of tumor immunity [idiotype network]). ADCC appears to be one of the most important immune effector functions. Antibodies may also induce apoptosis, cell cycle arrest, inhibition of cell proliferation as well as angiogenesis and metastatic spread. For most antibodies there is no clear dose-response relationship in vivo. The effect of antibodies can be enhanced by combination with chemotherapy and/or by agents which activate the immune system. The best therapeutic effect may be obtained if MABs are used early in the course of the disease. Rituximab (anti-CD20) was the first registered MAB for the therapy of follicular lymphoma. Impressive results have been seen in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) in follicular and high-grade lymphomas. In other non-Hodgkin's lymphoma subtypes, promising results are also seen in combination with chemotherapy. Trastuzumab (anti-Her2) is a breakthrough in the treatment of breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment. Alemtuzumab (anti-CD52) has shown impressive results both in refractory chronic lymphocytic leukemia and as up-front therapy. There are many other antibodies in late stages of testing for registration. Interesting MABs include cetuximab (anti-epidermal growth factor receptor [EGFR]), especially in combination with radiotherapy in head and neck cancer; ABX-EGF (anti-EGFR) in renal carcinoma; bevacizumab (anti-vascular endothelial growth factor) in several solid tumors. Antiepithelial cell adhesion molecule antibodies show promise in combination with chemotherapy in the adjuvant setting of colorectal carcinoma. It is estimated that about 20 antibodies will be in clinical use by the year 2010.
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PMID:Monoclonal antibodies in human cancer. 1498 43


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