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)

Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin beta1 (HRGbeta1) or transforming growth factor-alpha, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGbeta1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-alpha-stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGbeta1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGbeta1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGbeta1-enhanced phosphorylation of HER2 (Tyr(877)) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease.
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PMID:Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. 1723 69

Lung cancer is the most common cause of cancer mortality in male and female patients in the US. The etiology of non-small cell lung cancer (NSCLC) is not fully defined, but new data suggest that estrogens and growth factors promote tumor progression. In this work, we confirm that estrogen receptors (ER), both ERalpha and ERbeta, occur in significant proportions of archival NSCLC specimens from the clinic, with receptor expression in tumor cell nuclei and in extranuclear sites. Further, ERalpha in tumor nuclei was present in activated forms as assessed by detection of ER phosphorylation at serines-118 and -167, residues commonly modulated by growth factor receptor as well as steroid signaling. In experiments using small interfering RNA (siRNA) constructs, we find that suppressing expression of either ERalpha or ERbeta elicits a significant reduction in NSCLC cell proliferation in vitro. Estrogen signaling in NSCLC cells may also include steroid receptor coactivators (SRC), as SRC-3 and MNAR/PELP1 are both expressed in several lung cell lines, and both EGF and estradiol elicit serine phosphorylation of SRC-3 in vitro. EGFR and ER also cooperate in promoting early activation of p42/p44 MAP kinase in NSCLC cells. To assess new strategies to block NSCLC growth, we used Faslodex alone and with erlotinib, an EGFR kinase inhibitor. The drug tandem elicited enhanced blockade of the growth of NSCLC xenografts in vivo, and antitumor activity exceeded that of either agent given alone. The potential for use of antiestrogens alone and with growth factor receptor antagonists is now being pursued further in clinical trials.
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PMID:Estrogen receptor signaling pathways in human non-small cell lung cancer. 1727 70

Estrogen has been demonstrated to promote therapeutic reendothelialization after vascular injury by bone marrow (BM)-derived endothelial progenitor cell (EPC) mobilization and phenotypic modulation. We investigated the primary hypothesis that estrogen regulates physiological postnatal vasculogenesis by modulating bioactivity of BM-derived EPCs through the estrogen receptor (ER), in cyclic hormonally regulated endometrial neovascularization. Cultured human EPCs from peripheral blood mononuclear cells (PB-MNCs) disclosed consistent gene expression of ER alpha as well as downregulated gene expressions of ER beta. Under the physiological concentrations of estrogen (17beta-estradiol, E2), proliferation and migration were stimulated, whereas apoptosis was inhibited on day 7 cultured EPCs. These estrogen-induced activities were blocked by the receptor antagonist, ICI182,780 (ICI). In BM transplanted (BMT) mice with ovariectomy (OVX) from transgenic mice overexpressing beta-galactosidase (lacZ) regulated by an endothelial specific Tie-2 promoter (Tie-2/lacZ/BM), the uterus demonstrated a significant increase in BM-derived EPCs (lacZ expressing cells) incorporated into neovasculatures detected by CD31 immunohistochemistry after E2 administration. The BM-derived EPCs that were incorporated into the uterus dominantly expressed ER alpha, rather than ER beta in BMT mice from BM of transgenic mice overexpressing EGFP regulated by Tie-2 promoter with OVX (Tie-2/EGFP/BMT/OVX) by ERs fluorescence immunohistochemistry. An in vitro assay for colony forming activity as well as flow cytometry for CD133, CD34, KDR, and VE-cadherin, using human PB-MNCs at 5 stages of the female menstrual-cycle (early-proliferative, pre-ovulatory, post-ovulatory, mid-luteal, late-luteal), revealed cycle-specific regulation of EPC kinetics. These findings demonstrate that physiological postnatal vasculogenesis involves cyclic, E2-regulated bioactivity of BM-derived EPCs, predominantly through the ER alpha.
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PMID:Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis. 1765 79

Estrogen is a known immunomodulator with pleiotropic effects on macrophage function that partly accounts for the gender bias observed in numerous autoimmune, cardiovascular, and neurodegenerative disorders. The effect of estrogen on the survival of human macrophages is largely unknown, and in this study we demonstrate that 17beta-estradiol (E2) provokes a death response in human THP-1 macrophages by initiating Bax translocation from cytosol to the mitochondria; however, a concomitant up-regulation of Bcl-2 creates a Bax to Bcl-2 ratio favorable for Bcl-2, thus ensuring cell survival. Both Bcl-2 up-regulation and Bax translocation are estrogen receptor-dependent events; however, Bcl-2 augmentation but not Bax translocation is dependent on Ca(2+) increase, activation of protein kinase C, and ERK phosphorylation. This estrogen-induced Bcl-2 increase is crucial for the survival of THP-1 macrophages as well as that of human peripheral blood monocyte-derived macrophages, which is evident from E2-induced cell death under small interfering RNA-mediated Bcl-2 knockdown conditions. Hence, this study demonstrates that E2-induced Bcl-2 up-regulation is a homeostatic survival mechanism necessary for the manifestation of immunomodulatory effect of estrogen on human macrophages.
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PMID:Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. 1767 94

Rifalazil, a second-generation rifamycin, is being evaluated for the treatment of sexually transmitted disease and gastrointestinal infections. We determined whether rifalazil influences CYP3A4 metabolism by studying the effect of a single oral, 25 mg dose of rifalazil administered to healthy postmenopausal women, on the steady-state pharmacokinetics (PK) of ethinyl estradiol (EE) during administration of Ortho-Novum 1/35 (EE/NET). Noncompartmental PK and sequential statistical analyses were performed to establish if and when subjects achieved steady-state EE plasma concentrations and to determine whether this steady state was altered by rifalazil administration. The geometric mean ratios for the difference between EE alone and following rifalazil for EE Cmax, AUC(0-24) and Cmin were 105.9, 104.4 and 105.0, respectively. The 90% confidence intervals for each ratio fell within 80 - 125% of the reference treatment indicating no significant difference in the PK of EE before or after rifalazil administration. The posterior probabilities for the true treatment differences of Cmax or AUC(0-24) being less than 20% were > 99.99% in both cases. Based on the results of this study, there is no CYP3A4-metabolic interaction between a single oral, 25 mg dose of rifalazil and EE for either induction or inhibition. Consequently, there is minimal threat of contraceptive failure when single doses of rifalazil are administered with EE/NET. A single dose of rifalazil 25 mg was well tolerated when administered concomitantly with a combination oral contraceptive (EE/NET) by healthy postmenopausal females.
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PMID:Lack of effect of rifalazil on ethinyl estradiol pharmacokinetics in healthy postmenopausal women. 1772 49

Mouse cerebellar development occurs at late embryonic stages and through the first few weeks of postnatal life. Hormones such as 17-beta-estradiol (E2) have been implicated in cerebellar development, through the expression of E2 receptors (ER). However, the role of E2 in the development and function of cerebellar neurons has yet to be fully elucidated. To gain insight into E2's actions on the developing cerebellum, we characterized a cloned neuronal cell line, E(t)C.1, derived from late embryonic cerebellum for its neural properties and responsiveness to E2. Our results revealed that E(t)C.1 cells express markers characteristic of neural progenitor cells such as Nestin, Musashi, and Doublecortin (DCX), and of the granule cell lineage such as Math1 and Zipro1. The ER alpha and beta (ERalpha and ERbeta) were also identified in this cell line. Functionality of ERs was verified using an Estrogen Response Element (ERE)-Luciferase reporter plasmid. E2 modulated ERalpha, FMRP, and IL-6, which were expressed in these cells. However, E2 did not induce changes in neural proteins nor induce maturation of E(t)C.1 cells. CREB and ERK(1/2) protein kinases were not modulated by E2 either. Interestingly, E(t)C.1 expressed active p450 Aromatase (P450arom), which was confirmed by the aromatization of androstenedione (AD) to E2 and other estrogen metabolites. Collectively, our results show that the E(t)C.1 cell line may serve as a model to study early development of cerebellar progenitor granule cells, and their responsiveness to E2.
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PMID:Characterization of a cerebellar granule progenitor cell line, EtC.1, and its responsiveness to 17-beta-estradiol. 1798 Aug 64

Clinical and experimental studies have suggested that estrogens, the archetype of female hormones, participate in the control of male germ cell proliferation and that fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, the underlying mechanisms remain to be elucidated. 17beta-Estradiol (E2) conjugated to BSA was able to stimulate human testicular seminoma cell proliferation by triggering a rapid, nongenomic, membrane-mediated activation of ERK1/2 and cAMP-dependent protein kinase A (PKA). Both ERK1/2 and PKA participated in this promoting effect. This activation was associated with phosphorylation of the transcription factor cAMP response element-binding protein and the nuclear factor retinoblastoma protein. Enhanced proliferation together with ERK activation could be reversed by pertussis toxin, a G protein inhibitor. Estrogen receptors (ERs) in JKT-1 were characterized by immunofluorescence, subcellular fractioning, and Western blot. JKT-1 cells did not express ERalpha but ERbeta, which localized to the mitochondria and the nucleus but not to the membrane. Moreover, neither ICI-182,780, a classical ER antagonist, nor tamoxifen, a selective ER modulator, could reverse the 17beta-estradiol-BSA-induced promoting effect. Estrogens contribute to human testicular germ cell cancer proliferation by rapid activation of ERK1/2 and PKA through a membrane nonclassical ER. This nongenomic effect represents a new basis for understanding the estrogenic control of spermatogenesis and evaluating the role of fetal exposure to xenoestrogens during malignant transformation of testicular germ stem cells.
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PMID:Estrogens promote human testicular germ cell cancer through a membrane-mediated activation of extracellular regulated kinase and protein kinase A. 1803 75

A total of 211 cases of primary lung adenocarcinoma were tested for expression of gross cystic disease fluid protein-15 (GCDFP-15) and only 11 cases (5.2%) were positive. The cases occurred with an equal sex distribution in older individuals whose carcinomas were frequently identified on screening radiographs. The adenocarcinomas were peripheral lesions and had an average size of 2.9 cm (range, 1.1 to 7.0). Histologically, they were usually mixed acinar and papillary adenocarcinomas with abundant extracellular mucin production, with the neoplastic cells having a polygonal shape, round to oval nuclei, diffuse powdery chromatin, and abundant eosinophilic granular cytoplasm. Clear cells and apocrinelike cells with prominent central nucleoli were common. GCDFP-15 was expressed in conjunction with thyroid transcription factor-1 in 81% of cases and synaptophysin was seen in 65%. Estrogen and progesterone receptors were not expressed. EGFR gene amplification and mutations of exons 19 and 21 were rare. KRAS mutations and HER2 gene amplification were not seen. This report details the first 11 cases of pulmonary adenocarcinoma to express GCDFP-15 and their distinctive morphology with frequent mucin production and coexpression of thyroid transcription factor-1 and synaptophysin.
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PMID:Gross cystic disease fluid protein-(GCDFP-15): expression in primary lung adenocarcinoma. 1830 Aug 7

Endocrine treatment of breast cancer is widely applied and effective. However, in advanced disease cases, the tumors will eventually progress into an estrogen-independent and therapy-resistant phenotype. To elucidate the molecular mechanisms underlying this endocrine therapy failure, we applied retroviral insertion mutagenesis to identify the main genes conferring estrogen independence to human breast cancer cells. Estrogen-dependent ZR-75-1 cells were infected with replication-defective retroviruses followed by selection with the anti-estrogen 4-hydroxy-tamoxifen. In the resulting panel of 79 tamoxifen-resistant cell lines, the viral integrations were mapped within the human genome. Genes located in the immediate proximity of the retroviral integration sites were characterized for altered expression and their capacity to confer anti-estrogen resistance when transfected into breast cancer cells. Out of 15 candidate BCAR (breast cancer anti-estrogen resistance) genes, seven (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7, and TRERF1/BCAR2) were shown to directly underlie estrogen independence. Our results show that insertion mutagenesis is a powerful tool to identify BCAR loci, which may provide insights into the molecular and cellular mechanisms of breast tumor progression and therapy resistance thereby offering novel targets for the development of tailor-made therapeutical and prevention strategies.
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PMID:Functional identification of genes causing estrogen independence of human breast cancer cells. 1835 53

Estrogen has been reported to prevent development of cardiac hypertrophy in female rodent models and in humans. However, the mechanisms of sex steroid action are incompletely understood. We determined the cellular effects by which 17beta-estradiol (E2) inhibits angiotensin II (AngII)-induced cardiac hypertrophy in vivo. Two weeks of angiotensin infusion in female mice resulted in marked hypertrophy of the left ventricle, exacerbated by the loss of ovarian steroid hormones from oophorectomy. Hypertrophy was 51% reversed by the administration of E2 (insertion of 0.1 mg/21-d-release tablets). The effects of E2 were mainly mediated by the estrogen receptor (ER) beta-isoform, because E2 had little effect in ERbeta-null mice but comparably inhibited AngII-induced hypertrophy in wild-type or ERalpha-null mice. AngII induced a switch of myosin heavy chain production from alpha to beta, but this was inhibited by E2 via ERbeta. AngII-induced ERK activation was also inhibited by E2 through the beta-receptor. E2 stimulated brain natriuretic peptide protein expression and substantially prevented ventricular interstitial cardiac fibrosis (collagen deposition) as induced by AngII. Importantly, E2 inhibited calcineurin activity that was stimulated by AngII, related to E2 stimulating the modulatory calcineurin-interacting protein (MCIP) 1 gene and protein expression. E2 acting mainly through ERbeta mitigates the important signaling by AngII that produces cardiac hypertrophy and fibrosis in female mice.
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PMID:Estrogen inhibits cardiac hypertrophy: role of estrogen receptor-beta to inhibit calcineurin. 1837 23


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