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)

We describe a novel approach that allows detection of primary and metastatic cells in vivo in which either the extracellular signal-regulated kinase (ERK) or the p38 pathway is activated. Our recent findings showed that ERK and p38 kinases regulate, respectively, programs dictating cell proliferation (high ERK-to-p38 ratio) or growth arrest and dormancy (low ERK-to-p38 ratio) in vivo. Thus, we were able to use green fluorescent protein (GFP) to reflect ERK and p38 activities and, consequently, the proliferative state of cancer cells. This was accomplished by transfecting tumorigenic T-HEp3 and HT1080 cells, and dormant D-HEp3 cells, with plasmids coding for Elk-GAL4 or CHOP-GAL4 fusion proteins that, when phosphorylated by either ERK or p38, respectively, transactivated a GFP-reporter gene. The fate of these cells was examined in culture, in primary sites, and in spontaneous metastasis in chick embryos and nude mice. In culture GFP level was directly proportional to the previously established levels of ERK or p38 activation. In contrast, during the first 24 hours of in vivo inoculation, both the tumorigenic and the dormant cells strongly activated the p38 pathway. However, in the tumorigenic cells, p38 activity was rapidly silenced, correcting the ERK/p38 imbalance and contributing to high ERK activity throughout the entire period of tumor growth. In contrast, in the small nodules formed by dormant cells, the level of ERK activity was dramatically reduced, whereas p38 activity remained high. Strong activation of ERK was evident in metastatic sites, whereas p38 activation was silenced in this anatomic location as well. These results show that it is possible to directly measure cancer cell response to microenvironment with this reporter system and that only proliferation-competent cells have the ability to rapidly adapt ERK and p38 signaling for proliferative success. This approach allows isolation and further characterization of metastatic cells with specific signaling signatures indicative of their phenotypes.
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PMID:Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. 1549 54

Myxoid/round cell liposarcomas (MLS/RCLS) are characterized by chromosome translocations that result in formation of FUS-CHOP or EWSR1-CHOP fusion oncogenes. More than 95% of the tumors carry one of these fusion genes. FUS-CHOP transforms 3T3 cells and causes MLS/RCLS-like tumors in transgenic mice. The fusion oncoproteins act as abnormal transcription factors and are believed to induce abnormal expression of growth controlling genes as part of their transforming activities. The aim of this study was to search for recurrent abnormal expression patterns of cell cycle regulating proteins and growth factor receptors. A series of 14 MLS/RCLS, 2 MLS/RCLS derived cell lines and a FUS-CHOP transfected human sarcoma cell line were analyzed using immunohistochemistry, Western blotting, and cDNA microarray based screening. The results revealed a highly abnormal expression pattern of several growth controlling proteins. The G1 cyclins D1 and E and their associated kinases CDK4 and CDK2 were strongly overexpressed in all of the tumors. High expression levels were also found for Cdk4/6 inhibitor P16 and CDK2 inhibitors P27 and P57. The growth factor tyrosine kinase receptors PDGFRB and EGFR were present in most cells of all investigated tumors. We conclude that deregulation of G1 controlling proteins is common in MLS/RCLS and that aberrant expression of these proteins is of importance in the pathogenesis of this tumor type.
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PMID:Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas. 1549 25

It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.
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PMID:Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall. 1568 Nov 17

The retinoid-inducible gene 1 (RIG1) protein is a retinoid-inducible growth regulator. Previous studies have shown that the RIG1 protein inhibits the signaling pathways of Ras/mitogen-activated protein kinases. However, neither the mode of action nor the site of inhibition of RIG1 is known. This study investigated the effects of RIG1, and the mechanisms responsible for these effects, on the activation of Ras proteins in HtTA cervical cancer cells. RIG1 reduced the levels of activated Ras (Ras-GTP) and total Ras protein in cells transfected with mutated H-, N-, or K-Ras(G12V), or in cells transfected with the wild type H- or N-Ras followed by stimulation with epidermal growth factor. The half-life of Ras protein decreased from more than 36 h in control cells to 18 h in RIG1-transfected cells. RIG1 immunoprecipitated with the Ras protein in co-transfected cellular lysates. In contrast to the predominant plasma membrane localization in control cells, the H-Ras fusion protein EGFP-H-Ras was localized within a discrete cytoplasmic compartment where it co-localized with RIG1. RIG1 inhibited more than 93% of the Elk- and CHOP-mediated transactivation induced by H- or K-Ras(G12V). However, RIG1 did not inhibit the transactivation induced by MEK1 or MEK3, and failed to suppress the phosphorylation of extracellular signal-regulated kinases 1 and 2 induced by the constitutively activated B-Raf(V599E). The RIG1 with carboxyl terminal truncation (RIG1DeltaC) did not immunoprecipitate with Ras and had no effect on Ras activation or transactivation of the downstream signal pathways. These data indicate that RIG1 exerts its inhibitory effect at the level of Ras activation, which is independent of Ras subtype but dependent on the membrane localization of the RIG1 protein. This inhibition of Ras activation may be mediated through downregulation of Ras levels and alteration of Ras subcellular distribution.
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PMID:RIG1 inhibits the Ras/mitogen-activated protein kinase pathway by suppressing the activation of Ras. 1600 86

A 33-years-old man was diagnosed as having undifferentiated carcinoma presenting with right neck lymphadenopathy in December 2000. He obtained complete remission (CR) following chemotherapy, radiation and lymphadenectomy on the right neck. He had multiple para-aorta lymphadenopathy and splenomegaly in December 2001. An open-abdominal lymph node biopsy was performed from which a diagnosis of anaplastic large cell lymphoma was made. CR was achieved with biweekly CHOP, however, the patient suffered from a relapse twice. He underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-matched sister while in non-CR in November 2002. Engraftment was achieved on day 14, and at the same time, complete chimerism was confirmed. Acute grade III graft-versus-host disease (GVHD) developed and was controlled with cyclosporine A and prednisolone. Extensive chronic GVHD was subsequently observed and required systemic immunosuppression. His condition returned to CR after the PBSCT and he sustained complete chimerism. He suddenly died of fulminant thrombotic microangiopathy seven months after the PBSCT. The tumor cells were ALK-positive, CD30-negative and JH rearrangement was detected, and were therefore classified as diffuse large B-cell lymphoma with expression of ALK according to the WHO classification, though they differed from this subtype in some points. Although this case was refractory for chemotherapy with a complex karyotype, the graft-versus-lymphoma effect might have contributed to the sustained CR following the PBSCT.
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PMID:[CD30-negative diffuse large B-cell lymphoma expressing ALK]. 1644 Jul 42

Rituximab in combination with chemotherapy (immunochemotherapy) is one of the most effective treatments available for follicular lymphoma (FL). This study aimed to determine whether differences in gene expression in FL tissue correlate with outcome in response to rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (R-CHOP). We divided 24 patients into long- [time to treatment failure (TTF) >35 months] and short-term (TTF <23 months) responders, and analysed the gene expression profiles of lymphoma tissue using oligonucleotide microarrays. We used a supervised learning technique to identify genes correlating with outcome, and confirmed the expression of selected genes with quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Among the transcripts with a high correlation between microarray and qPCR analyses, we identified EPHA1, a tyrosine kinase involved in transepithelial migration, SMAD1, a transcription factor and a mediator of bone morphogenetic protein and transforming growth factor-beta signalling, and MARCO, a scavenger receptor on macrophages. According to Kaplan-Meier estimates, high EPHA1, and low SMAD1 and MARCO expression were associated with better progression-free survival (PFS). Immunohistochemistry showed that EphA1 was primarily localised in granulocytes. In addition, both EphA1 and Smad1 were expressed in vascular endothelia. However, no difference in vasculature was detected between long- and short-term responders. In a validation set of 40 patients, a trend towards a better PFS was observed among patients with high EphA1 expression. We conclude that gene expression in non-malignant cells contributes to clinical outcome in R-CHOP-treated FL patients.
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PMID:Differential gene expression in non-malignant tumour microenvironment is associated with outcome in follicular lymphoma patients treated with rituximab and CHOP. 1692 74

We report detailed clinical and pathologic features of four cases of anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL), a rare entity with only 29 currently reported cases. This study is the third largest of all reported series. Biopsies from four adult patients aged 41, 49, 53, and 71 years (three lymph nodes and one nasopharyngeal mass) exhibited immunoblastic/plasmablastic morphology. By immunohistochemistry and/or flow cytometry, they expressed cytoplasmic ALK-1, CD138, VS38 (3/3), monoclonal cytoplasmic light chain, CD45, EMA, CD4, and CD57 (2/3), and were negative for CD3, CD30, CD56, and TIA-1. Two showed variable CD79a expression, and one had rare CD20(+) cells. Two of three cases exhibited rare CD43(+) reactivity. One case showed scattered cytokeratin(+) cells, which could possibly lead to a misdiagnosis of carcinoma. After CHOP and radiotherapy, two stage I patients were free of disease at 58 and 36 months, whereas a stage IV patient was dead of disease at 22 months.
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PMID:ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. 1727 65

Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the beta(1)-adrenergic receptor (beta(1)-EC(II)) is mediated via a biologically active anti-beta(1)-EC(II) antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the beta(1)-EC(II) autoantibody is a partial beta(1)-agonist, we speculate that the cardiomyopathy is produced by the beta(1)-receptor-mediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive beta(1)-EC(II) immunization, sham immunization, NE pellet, or beta(1)-EC(II) immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferase-mediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. beta(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the beta(1)-EC(II) antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by beta(1)-EC(II) peptide, and this is enhanced by increased NE and caused by activation of the beta(1)-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.
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PMID:Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine. 1754 81

Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBPalpha-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.
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PMID:ER stress triggers apoptosis by activating BH3-only protein Bim. 1760 22

With the introduction of rituximab to chemotherapy in lymphoma, CHOP changed to R-CHOP in elderly, intermediate risk DLBCL (diffuse large B-cell lymphoma) patients. Although the treatment is not yet standard, due to insufficient evidence, in clinical practice it is an R-containing regimen, for example, in mantle cell lymphoma, such as HyperCVAD/MA to R-HyperCVAD/MA. Recently, another group and ours reported the presence of rituximab resistance during R-containing chemotherapy. If the lymphoma is bulky,the overexpression of CD 55 (complement regulatory molecule) leads to resistance to rituximab. When the patients evidenced the loss of CD 20 antigen in refractory/relapsed lymphoma after R-containing therapy, some patients showed the presence of CD 20 point mutation. In the cases of refractory/relapsed cases, radioimmunotherapy or other monoclonal antibodies are prepared, including Zevalin and CD 22, CD 40, CD 74, and HLA-DR targeting antibodies. Not only monoclonal antibodies but also HDACI or bortezomib (NF-kappaB) and other signal inhibitors (for Akt, ERK/MAPK) have been developed. In Japan, we must consider the higher speed of infusion rituximab and we must prepare standard therapy for lymphoma because of recruiting phase I/II clinical trials after use of rituximab for easy entry.
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PMID:[Recent progress in rituximab therapy and its resistance--how do we overcome?]. 1768 98


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