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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effects of protein kinase-C (PKC) activation on expression of the six known insulin-like growth factor-binding proteins (IGFBPs) by human endometrial carcinoma cells. Each of six known IGFBPs was expressed in one or more of the three cell lines examined. The addition of 10(-7) M 4 beta-phorbol 12-myristate 13-acetate (PMA) to HEC-50 and HEC-1B cells resulted in changes in cell morphology, growth inhibition, activation of PKC, and an increase in expression of IGFBP-1. PMA had no effect on these parameters in the Ishikawa cell line, which did not express IGFBP-1. In HEC-50 cells, the effect of PMA was blocked by the concomitant addition of the PKC inhibitor staurosporin and the simultaneous addition of cycloheximide. PMA also resulted in an increase in IGFBP-3 in HEC-50 cells and an increase in IGFBP-6 expression in HEC-1B cells. In contrast, IGFBP-3 expression was down-regulated by PMA in HEC-1B and Ishikawa cells. The abundance of IGFBP-2 and IGFBP-5 mRNAs was also reduced in HEC-1B and Ishikawa cells, respectively. IGFBP-4 was expressed only in HEC-50 cells and was not affected by PMA treatment. These data establish a role for the PKC pathway in regulation of expression of IGFBP-1, -2, -3, and -5 in endometrial adenocarcinoma cells and illustrate the complexity of cell type-specific expression of the IGFBPs.
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PMID:Phorbol esters differentially regulate the expression of insulin-like growth factor-binding proteins in endometrial carcinoma cells. 128 Feb 5

Epidermal growth factor reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estrogen-induced growth and differentiation. The mechanism by which the actions of estrogens and epidermal growth factor (EGF) converge is unknown. The studies described herein were performed to investigate the possibility that some of the actions of EGF may be mediated through the estrogen receptor. A specific estrogen receptor (ER) antagonist inhibited estrogenlike effects of EGF in the mouse uterus, specifically induction of DNA synthesis and phosphatidylinositol turnover. In addition, EGF elicited enhanced nuclear localization of uterine ER and formation of a unique nuclear form of ER that is present after estrogen treatment. These in vivo observations indicated that EGF may elicit some of its actions by activation of nuclear ER. Thus, the effect of peptide growth factors on activation of a consensus estrogen response element was assessed in Ishikawa human endometrial adenocarcinoma cells, which contain negligible ER levels, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ER. EGF and TGF alpha induced transcriptional activation of a consensus estrogen response element (ERE) in an ER-dependent manner in both cell types. In addition, insulinlike growth factor I (IGF-I) was as potent as 17 beta-estradiol in BG-1 cells. Synergism between growth factors and estrogen was observed in both cell types, although synergism was not observed between the different classes of growth factors [i.e., transforming growth factor alpha (TGF alpha) and IGF-I] in BG-1 cells. The most potent activator of ERE-dependent transcription was a protein kinase C activator (TPA), which acted synergistically with 17 beta-estradiol. A protein kinase C inhibitor abolished the effect of TPA but not that of 17 beta-estradiol, IGF-I, or TGF alpha. A protein kinase A activator elicited ER-dependent activation of transcription and did not synergize with estrogen or growth factors. In conclusion, some physiologic actions of peptide growth factors are dependent on ER. Indeed, growth factors are capable of eliciting ER-dependent activation of an ERE. Both the protein kinase A and protein kinase C pathways can elicit ER-dependent transcriptional activation; however, it is unlikely that these pathways mediate the effects of peptide growth factors on the ER in BG-1 cells.
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PMID:Cross talk between peptide growth factor and estrogen receptor signaling systems. 859 72

We have investigated F-actin and the integrin fibronectin receptor as possible targets of tamoxifen (TAM) signaling in a cell-based model of the endometrium. Normal human endometrial stromal cells and RL95-2 human endometrial adenocarcinoma cells were treated for 1 h with TAM, a known antagonist of protein kinase C (PKC), or with staurosporine or HA1004, two broad-spectrum protein kinase antagonists capable of inhibiting PKC and PKA, respectively. We utilized fluorescein-phalloidin and confocal microscopy to visualize the cellular distribution of F-actin. Normal stromal cells and RL95-2 cells differed in the arrangement of F-actin in control cells and in their response to TAM. In control stromal cells, actin stress fibers were well organized throughout the cell, but in RL95-2 cells, they were disorganized and present mainly at the cell periphery. F-actin in RL95-2 cells treated with TAM (0.1 and 1.0 microM) or with staurosporine (0.7 and 7.0 nM) exhibited a reorganization into stress fibers consistent with a more stationary phenotype. In contrast, TAM- or staurosporine-treated normal stromal cells exhibited an increase in the amount of organized F-actin. Interestingly, in normal stromal cells treated with staurosporine but not TAM or HA1004, these F-actin fibers appeared to terminate in dense plaques proximal to the plasma membrane. The alpha 5/beta 1 integrin fibronectin receptor mediates between the extracellular matrix and the actin cytoskeleton. TAM induced clustering of the fibronectin receptor at the plasma membrane in normal stromal cells, but not in carcinoma cells. This study supports the importance of plasma membrane-cytoskeletal protein interactions in the response of normal and carcinoma cells to TAM.
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PMID:Tamoxifen alters the localization of F-actin and alpha 5/beta 1-integrin fibronectin receptors in human endometrial stromal cells and carcinoma cells. 939 40

The activation of mitogen-activated protein kinase (MAP kinase) and the regulation of cyclooxygenase 2 (COX-2) were investigated in the human endometrial adenocarcinoma cell line HEC-1B by treatment with platelet-activating factor (PAF) and hCG. Pre-treatment of the cells with both oestradiol and medroxyprogesterone acetate was required for MAP kinase activation and COX-2 expression to respond to PAF and hCG. PAF-induced MAP kinase activation was sensitive to MAP kinase kinase (MEK) inhibitor, PD098059, and phosphatidylinositol-3-OH kinase (PI3K) inhibitor, wortmannin. In contrast, hCG-induced MAP kinase activation was sensitive to PD098059 and protein kinase A inhibitor, H-89, but not to wortmannin. PAF-induced COX-2 expression was insensitive to PD098059 but sensitive to wortmannin, whereas hCG-induced COX-2 expression was sensitive to PD098059 and H-89 but insensitive to wortmannin. 8-(4-chlorophenylthio)-cAMP, a potent cAMP analogue, induced activation of MAP kinase and expression of COX-2. These results indicate that MAP kinase is activated with PAF and hCG in HEC-1B cells. In addition, COX-2 expression is stimulated through the MAP kinase activation pathway with hCG and the wortmannin sensitive pathway with PAF in HEC-1B cells. These results also imply that protein kinase A remains upstream of hCG-induced activation of MAP kinase in HEC-1B cells.
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PMID:Mitogen-activated protein kinase activation and regulation of cyclooxygenase 2 expression by platelet-activating factor and hCG in human endometrial adenocarcinoma cell line HEC-1B. 1064 45

The regulation of expression of cyclooxygenase 2 (COX-2) was investigated by treatment with PGE(2) in human endometrial adenocarcinoma cell line HEC-1B. One microM PGE(2) could stimulate the expression of COX-2 approximately twofold in this cell line. The same concentration of PGE(2) also stimulated activation of mitogen-activated protein kinase (MAP kinase) and protein kinase B (PKB). PGE(2)-induced MAP kinase activation was sensitive to a MAP kinase kinase (MEK) inhibitor, PD098059, and a protein kinase A inhibitor, H-89. PD098059 and H-89 also partially inhibited the expression of COX-2 stimulated by PGE(2). PGE(2) could stimulate the activation of PKB, which was sensitive to phosphatidylinositol-3-OH kinase (PI3K) inhibitor, wortmannin. Whereas wortmannin alone partially inhibited the expression of COX-2, a combination of wortmannin and PD098059 totally inhibited PGE(2)-mediated COX-2 expression. These results suggest that MAP kinase and PI3K pathways are stimulated with PGE(2), and that both of these pathways are involved in the expression of COX-2. In addition, they also suggest that protein kinase A remains upstream of PGE(2)-induced activation of MAP kinase in HEC-1B cells.
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PMID:Expression of cyclooxygenase 2 by prostaglandin E(2) in human endometrial adenocarcinoma cell line HEC-1B. 1095 41

Prostaglandin (PG) E(2) E-series prostanoid-2 (EP2) receptor is elevated in numerous carcinomas including the endometrium and has been implicated in mediating the effects of PGE(2) on vascular function. In this study, we investigated the intracellular signaling pathways that are activated by the EP2 receptor and their role in regulation of the expression of vascular endothelial growth factor in endometrial adenocarcinoma (Ishikawa) cells. Ishikawa cells were stably transfected with EP2 receptor cDNA in the sense or antisense directions. Treatment of Ishikawa cells with PGE(2) rapidly induced transactivation of the epidermal growth factor receptor (EGFR) and activation of ERK1/2 via the EP2 receptor. Preincubation of cells with chemical inhibitors of protein kinase A, c-Src, and EGFR kinase abolished the EP2-induced activation of EGFR and ERK1/2. PGE(2) signaling via the EP2 receptor also promoted the mRNA expression and secretion of vascular endothelial growth factor protein in Ishikawa cells. This effect was inhibited by preincubation with chemical inhibitors of EGFR kinase, ERK1/2 signaling, and small inhibitory RNA molecules targeted against the EGFR. Therefore, we have demonstrated that elevated EP2 receptor expression may facilitate the PGE(2)-induced release of proangiogenic factors in reproductive tumor cells via intracellular cAMP-mediated transactivation of the EGFR and ERK1/2 pathways.
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PMID:Elevated prostaglandin EP2 receptor in endometrial adenocarcinoma cells promotes vascular endothelial growth factor expression via cyclic 3',5'-adenosine monophosphate-mediated transactivation of the epidermal growth factor receptor and extracellular signal-regulated kinase 1/2 signaling pathways. 1504 90

There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.
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PMID:Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? 1680 39

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) play an important role in the development and maintenance of male and female gonads. Both these hormones act through the same specific receptor LH/hCG receptor (LHR). Recent studies have shown the existence of functional LHR in several non-gonadal tissues. The aim of this study was to confirm the functional existence of LHR in an endometrial adenocarcinoma cell line, Ishikawa cells, which has been used since long as an in vitro uterine endometrium model. Reverse transcriptase-polymerase chain reaction (RT-PCR) data showed the stable expression of LHR in this cell line. However, the receptor failed to activate the PKA pathway in response to hCG, which is the most conventional mode of LH/hCG action in target tissues. When tested for other pathways, hCG failed to activate them either. Nested RT-PCR confirmed the existence of full-length LHR and this was further supported by Western blot. This study demonstrated that although Ishikawa cells do possess a full-length LHR, which was confirmed by RT-PCR, nested RT-PCR, Western blot and DNA sequencing, it failed to activate the conventional LH-mediated downstream signaling. Based on these data we hypothesize that in Ishikawa cells LH/hCG does not utilize its conventional receptor. Whether it acts through some other receptor is a question, which can be answered through future research.
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PMID:Assessment of luteinizing hormone receptor function in an endometrial cancer cell line, Ishikawa cells in response to human chorionic gonadotrophin (hCG). 1754 47

In endometrial adenocarcinomas COX-2 and F-series prostanoid (FP) receptor expression and prostanoid biosynthesis (PGE(2) and PGF(2alpha)) are elevated. In the present study, we investigated the effect of PGE(2) and PGF(2alpha) on the expression of COX-2 via the FP receptor in endometrial adenocarcinoma cells stably expressing the FP receptor (FPS cells). Using chemical inhibitors of intracellular signaling pathways, reporter gene assays and quantitative RT-PCR analysis, we show that PGE(2) and PGF(2alpha) can mobilize inositol 1,4,5-trisphosphate, induce ERK1/2 phosphorylation via the phospholipase Cbeta-protein kinase A-epidermal growth factor receptor pathway and induce cyclooxygenase-2 (COX-2) expression via the FP receptor. In addition we show that the PGE(2) or PGF(2alpha)-regulation of COX-2 via the FP receptor is mediated via the cAMP response element (CRE) binding site on the COX-2 promoter. These data indicate that PGE(2) and PGF(2alpha) biosynthesized locally within endometrial adenocarcinomas can regulate tumor cell function in an autocrine/paracrine manner via the FP receptor.
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PMID:Prostaglandin E2 and F2alpha activate the FP receptor and up-regulate cyclooxygenase-2 expression via the cyclic AMP response element. 1831 57

We evaluated whether inhibition of heat shock protein 90 (hsp90) function by novobiocin derivatives could induce the degradation of signal transducers that drive cancer cell growth and thereby promote apoptosis. Removal of the noviose moiety in novobiocin and introduction of a tosyl substituent at C-4 or C-7 coumarin nucleus provided derivatives 4TCNA and 7TCNA which compared favourably with novobiocin in MCF-7 breast cancer cells. Here we extend the antiproliferative and apoptotic properties of these analogues to a panel of cancer cell lines. Destabilization of hsp90 client proteins Raf-1, HER2, and cdk4 suggests inhibition of hsp90 chaperoning function. In HT29 colon and IGROV1 ovarian cancer cells, the growth inhibiting effect of 4TCNA and 7TCNA was consistent with the stimulation of cell death as assessed by the processing and activation of caspase 9, 8, 7 and 3 and the subsequent cleavage of poly(ADP-ribose) polymerase (PARP). In Ishikawa endometrial adenocarcinoma cells, 4TCNA also promoted apoptosis and the processing of PARP. These derivatives impacting multiple pathways involved in the neoplastic process may represent promising drugs for cancer therapy.
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PMID:Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells. 1884 35


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