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)

An important recent advance in anticancer therapy was the development of molecular-targeting drugs, such as the epidermal growth-factor receptor (EGFR)-targeting drug ZD1839 (Iressa) and the HER2-trageting anti-HER2 monoclonal antibody trastuzumab (Herceptin). ZD1839 and trastuzumab are reported to improve the therapeutic efficacy of treatment for non-small-cell lung cancer (NSCLC) and breast cancer, respectively, although the effectiveness of either drug alone is not satisfactory. NSCLC cells often express both EGFR and HER2. We therefore investigated whether a combination of ZD1839 and trastuzumab had an additive or synergistic antitumor effect. In culture ZD1839 inhibited the growth of four NSCLC cell lines (A549, NCI-H23, NCI-H727, and NCI-H661) that expressed various levels of EGFR, HER2, HER3, and HER4. A significant cytotoxic effect was observed when ZD1839 was combined with trastuzumab in A549 cells. However, this combination had no apparent effect in NCI-H23 cells. Significant G(1)-phase arrest, increased p27 expression and decreased cyclin E or D1 levels were detected in A549 cells treated with ZD1839 and trastuzumab. No significant effects were detected in NCI-H23 cells examined. The combination treatment significantly inhibited the phosphorylation of EGFR, HER2, retinoblastoma, extracellular signal-regulated kinase-1/2, and protein kinase B/Akt in A549 cells, but not in NCI-H23 cells. Our results indicated that increased levels of constitutive EGFR/HER2 heterodimers were formed in A549 cells in the presence of ZD1839, whereas no heterodimer formation was detected in NCI-H23 cells. We therefore suggest that combination treatment with ZD1839 and trastuzumab might have improved therapeutic efficacy against NSCLC cells expressing both EGFR and HER2.
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PMID:Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. 1625 59

Cyclins are the regulatory subunits of kinases that control progress through the cell cycle. This review focuses on cyclins that are targets for extracellular signaling and frequently deregulated during oncogenesis, particularly cyclin D1. Receptor tyrosine kinases and adhesion molecules act through various effector pathways to modulate cyclin D1 abundance at multiple levels including transcription, translation and protein stability. In contrast, cyclin E-Cdk2 activity appears to be more commonly regulated by means other than regulation of cyclin E abundance. The importance of these pathways during oncogenesis is illustrated by the dependence of oncogenes such as Ras and Neu/ErbB2 on cyclin D1. Thus, understanding the roles of cyclins in growth factor and adhesion signaling is important for understanding the biology of both normal and neoplastic cells.
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PMID:Cyclins: roles in mitogenic signaling and oncogenic transformation. 1639 91

Unregulated FGF signaling produced by activating FGFR3 mutations causes several forms of dwarfism-associated chondrodysplasias in humans and mice. FGF signaling inhibits chondrocyte proliferation by activating multiple signal transduction pathways that all contribute to chondrocyte growth arrest and induction of some aspects of differentiation. Previous studies had identified the Stat1 pathway, dephosphorylation of the Rb family proteins p107 and p130, induction of p21 expression and sustained activation of MAP kinases as playing a role in the FGF response of chondrocytes. We have examined the role of Akt (PKB) in the response of chondrocytes to FGF signaling. Differently from what is observed in many other cell types, FGF does not activate Akt in chondrocytes, and Akt phosphorylation is actually downregulated after FGF treatment. By expressing a constitutively activated, myristylated form of Akt (myr-Akt) in the RCS chondrosarcoma cell line, we show that Akt activation partially counteracts the inhibitory effect of FGF signaling. The response of myr-Akt expressing cells to FGF is identical to parental RCS in the first few hours after treatment, but then diverges as myr-Akt cells show decreased p130 phosphorylation, increased cyclin E/cdk2 activity and continue to proliferate at a slow rate. Constitutive Akt activation does not affect p21 expression but appears to influence directly cdk/cyclin activity. On the other hand, the induction of differentiation-related genes is unchanged in myr-Akt cells. These results identify Akt downregulation as an important aspect of the response of chondrocytes to FGF that, however, only affects chondrocyte proliferation and not the ability of FGF to induce differentiation genes.
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PMID:Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes. 1652 91

In this paper we have explored the role of different kinase pathways of signal transduction in proliferation control of E1A + Ras transformants, using specific inhibitors of MAP-kinases ERK, JNK, p38 and PI3-kinase. According to our data, suppression of signalling cascades driven by RI3K only arrested proliferation of E1A + Ras cells, while suppression of either MAP-kinase did not lead to noticeable antiproliferative effect. We have shown that suppression of RI3K with LY294002 gave rise to accumulation of cyclin-dependent kinase inhibitor p27(KiP1) but not p21(Waf1). Accumulation of p27(KiP1) in LY294002-treated E1A + Ras cells was accompanied by a decrease in Cyclin E-Cdk2 and Cyclin A-Cdk2 activity, which caused diminution of Rb phosphorylation and strengthening of E2F-Rb binding. Binding of E2F with hypophosphorylated Rb resulted in inhibition of E2F activity and reduction of E2F-regulated gene transcription, these genes being necessary for S-phase entry and DNA synthesis. Thus, RI3K--Akt cascade plays the key role in maintenance of autonomous proliferation of cells transformed with E1A and cHa-ras oncogenes. Inhibition of PI3K leads to p27(Kip1) accumulation and cell cycle arrest, consequently.
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PMID:[The role of different kinase pathways of signal transduction in proliferation of E1A + Ras transformants]. 1670 95

To identify oncogene amplification involved in ovarian carcinogenesis, we studied 21 ovarian carcinomas and 5 serous borderline tumors using conventional comparative genomic hybridization (CGH) and CGH to a genomic DNA microarray. Immunohistochemical analysis of the proteins encoded by the genes that were amplified frequently (FGF3/4, FGFR1, CCNE1, PAK1, JUNB, and MDM2) was performed on a tissue microarray comprising 254 cases of ovarian neoplasms. Regarding histologic type, characteristic patterns of copy number changes were revealed. They correlated with histologic tumor type and with intratumoral heterogeneity. Gain of FGF3/4 and CCNE1 was found in all serous carcinomas. Endometrioid carcinomas most frequently showed gain of JUNB (83%), KRAS2 (67%), MYCN (50%), ESR (50%), and CCND2 (50%). Of the serous borderline tumors, 80% harbored amplification of FGFR1 and MDM2 and a 75% gain of PIK3CA. Only CCNE1 immunoreactivity was significantly correlated with CGH results (P < .05) and postoperative survival (P < .05). Microarray-based genomic analysis in combination with immunohistochemical analysis was found to be a powerful technique for identification of clinically relevant gene amplification in human ovarian cancer.
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PMID:Analysis of gene amplification and prognostic markers in ovarian cancer using comparative genomic hybridization for microarrays and immunohistochemical analysis for tissue microarrays. 1675 89

The main objective of this retrospective study was to investigate relations between cyclin E and pathoclinical factors in patients with operable breast cancer. Expression of cyclin E was analyzed by immunohistochemistry in specimens of invasive ductal breast cancer tissue obtained from 189 women during radical mastectomy. Overall, 110 tumor samples were regarded to be cyclin E positive. Cyclin E expression was more often seen in tumors with: negative steroid receptor status (p<0.0001), higher proliferative index (p=0.0014), higher tumor grade (p=0.0017), and presence of HER2 (p=0.0171). With a median follow-up of 58 months, expression of cyclin E together with negative steroid receptor status determined poor prognosis with a 5-year cancer-specific survival rate of 58%. It differed significantly from a survival curve of cyclin E negative and steroid receptor positive patients (87%, p=0.0005). No significant difference was observed in comparison with survival of cyclin E positive and steroid receptor positive patients (68%, p=0.221). We demonstrated that cyclin E expression in breast cancer cells was associated with negative steroid receptor status, HER2 presence, higher tumor grade and higher proliferation index. Expression of cyclin E together with lack of steroid receptors determined poor prognosis.
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PMID:Cyclin E expression in breast cancer correlates with negative steroid receptor status, HER2 expression, tumor grade and proliferation. 1676 19

The anti-HER2 antibody trastuzumab (Herceptin) has been used to treat patients with breast cancers that overexpress HER2. We have demonstrated that p27(Kip1) upregulation is one of the key events that cause G(1) arrest upon trastuzumab treatment. Here, we have examined the effect of trastuzumab on expression of CDK2, Rb, E2F, NPAT and histone H4 in breast cancer cells that overexpress HER2. Trastuzumab treatment dramatically inhibited the kinase activity and expression of CDK2, whereas the kinase activity and expression of CDK4 were not affected. Unlike the p27(Kip1) upregulation that occurs primarily through post-translational mechanisms, CDK2 was downregulated primarily at a transcriptional level as shown by Northern blotting and real-time RT-PCR analyses. With a decrease in CDK2 activity, trastuzumab decreased the kinase activity of cyclin E but had little effect on cyclin E protein level. Overexpression of wild-type cyclin E or its lower molecular weight forms did not influence the response to trastuzumab. Levels and activities of CDK6, cyclin A, and cyclin D1 were all suppressed by trastuzumab. As a result, trastuzumab inhibited Rb phosphorylation that associates with CDK2, cyclin E, CDK6, cyclin A, or cyclin D1. As predicted from these changes, trastuzumab decreased the DNA-binding activity of E2F, decreased the level of NPAT protein, and decreased the level of histone H4 mRNA. Blockade of the PI3K pathway with LY294002 produced similar effects to trastuzumab treatment on expression of each of these genes. Taken together, treatment of breast cancer cells that overexpress HER2 with the anti-HER2 antibody trastuzumab inhibits CDK2, Rb phosphorylation, E2F activity, NPAT, and histone H4 via PI3K signaling that are needed for both DNA and histone synthesis during progression from G(1) phase to S phase of the cell cycle.
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PMID:Anti-HER2 antibody trastuzumab inhibits CDK2-mediated NPAT and histone H4 expression via the PI3K pathway. 1686 13

MEK/ERK pathways are frequently activated in acute myelogenous leukemia, and this signal pathway's inhibitor has made it an interesting candidate for cancer chemotherapy. Little is known, however, about the effects of cellular and molecular mechanisms on human leukemic U937 cells. In the present study, we found that treatment with PD98059 significantly arrests the G1 phase through up-regulation of cyclin-dependent kinase (Cdk) inhibitor, and produces morphological features of apoptosis in U937 cells, which were associated with poly(ADP-ribose)polymerase (PARP) cleavage and PLC-gamma1 degradation. PD98059 also decreased the Cdk-2, Cdk-4, cyclin D1, and cyclin E expression, and increased high levels of the mitotic inhibitors p16(INIa), p21(Waf1), and p27(Kip1). Also, Bcl-2's overexpression and a caspase-3 inhibitor z-DEVD-fmk significantly attenuated PD98059-induced apoptosis through the down-regulation of caspase-3 activity, but did not attenuate G1 phase arrest. Moreover, PD98059 down-regulated Akt phosphorylation and produced a synergy effect of apoptosis with LY294002 co-treatment. Thus, our results imply that PD98059-induced apoptosis is significantly involved in down-regulation of Bcl-2, caspase-3 activity, the Akt pathway, and some of the biological functions in U937 cells.
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PMID:PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway. 1716 15

DNA microarrays have the potential to classify tumors according to their transcriptome. Tissue microarrays (TMAs) facilitate the validation of biomarkers by offering a high-throughput approach to sample analysis. We reanalyzed a high profile breast cancer DNA microarray dataset containing 96 tumor samples using a powerful statistical approach, between group analyses. Among the genes we identified was centromere protein-F (CENP-F), a gene associated with poor prognosis. In a published follow-up breast cancer DNA microarray study, comprising 295 tumour samples, we found that CENP-F upregulation was significantly associated with worse overall survival (p<0.001) and reduced metastasis-free survival (p<0.001). To validate and expand upon these findings, we used 2 independent breast cancer patient cohorts represented on TMAs. CENP-F protein expression was evaluated by immunohistochemistry in 91 primary breast cancer samples from cohort I and 289 samples from cohort II. CENP-F correlated with markers of aggressive tumor behavior including ER negativity and high tumor grade. In cohort I, CENP-F was significantly associated with markers of CIN including cyclin E, increased telomerase activity, c-Myc amplification and aneuploidy. In cohort II, CENP-F correlated with VEGFR2, phosphorylated Ets-2 and Ki67, and in multivariate analysis, was an independent predictor of worse breast cancer-specific survival (p=0.036) and overall survival (p=0.040). In conclusion, we identified CENP-F as a biomarker associated with poor outcome in breast cancer and showed several novel associations of biological significance.
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PMID:CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer. 1720 17

TNF-alpha induces some proinflammatory cytokines including IL-1beta, IL-6, IL-8, and itself by activation of NF-kappaB or MAPKs (p38, JNK, ERK). These cytokines play important roles in various inflammatory skin diseases, such as psoriasis. Recently it was also reported that expression of cyclin E is up-regulated by ERK pathway after TNF-alpha treatment. However, it was unknown whether curcumin, showing inhibitory effects on NF-kappaB and MAPKs, attenuates the expression of TNF-alpha-induced IL-1beta, IL-6, IL-8, and TNF-alpha as well as cyclin E expression in HaCaT cells. In this study, we investigated the inhibitory effect of curcumin on expression of proinflammatory cytokines and cyclin E in TNF-alpha-treated HaCaT cells. We found that curcumin inhibited the expression of TNF-alpha-induced IL-1beta, IL-6, and TNF-alpha, but not IL-8, in TNF-alpha-treated HaCaT cells as well as the TNF-alpha-induced cyclin E expression. In addition, curcumin inhibited the activation of MAPKs (JNK, p38 MAPK, and ERK) and NF-kappaB in TNF-alpha-treated HaCaT cells. Taken together, curcumin exerts anti-inflammatory and growth inhibitory effects in TNF-alpha-treated HaCaT cells through inhibition of NF-kappaB and MAPK pathways.
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PMID:Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. 1727 96


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