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)

Protein tyrosine kinases have been implicated in tumor initiation and progression. Here we used Northern blotting to study expression of their genes in cultured normal melanocytes and 19 melanoma cell lines from different stages of tumor progression. We detected transcripts for 2 cytoplasmic (ABL and FES) and 6 receptor (ECK, ERB-B2, FGF-R4, IGFI-R, KDR and TIE) kinases but not for receptors RET or TRK-A. Genes for ECK, FGF-R4 and TIE were expressed ectopically in melanomas (not in normal melanocytes). Similarly, ECK protein was detected by immunoblotting in metastatic melanomas but not in normal melanocytes. ECK mRNA levels tended to increase again during late melanoma progression. ECK and TIE mRNAs were also detected in highly metastatic variant cells but not in the corresponding poorly metastatic parental lines. Conversely, FES and KDR gene expression was lost in most advanced primary and metastatic melanomas. These findings suggest positive and negative roles for specific tyrosine kinases during progression.
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PMID:Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. 781 45

We have used the polymerase chain reaction and Northern blotting to identify protein tyrosine kinases that may play an important role in the process of melanoma initiation and progression. Degenerate primers from the conserved catalytic domain of tyrosine kinase genes were used to amplify and clone partial cDNA sequences from a human melanoma cell line (DX3-LT5.1) and normal human melanocytes. When the melanoma reaction products were sequenced, 13 distinct clones were found, of which one is novel to date and has provisionally been named MEK (for melanocytic kinase). Of the remaining 12 known kinases, only two, ERB-B2 and IGF1-R, have previously been reported in pigment cells. Reaction products from melanocytes included only eight of these 13 sequences. To test for quantitative differences in tyrosine kinase expression between normal and malignant cells, a panel of eight melanoma lines and normal melanocytes was analyzed by Northern blotting. Two tyrosine kinases (JTK-14/TIE and TYRO-9) were detected in some melanomas but were not found in normal melanocytes, whereas others, including MEK, appeared to be overexpressed in some malignant lines. A minority of kinases showed either no change or a reduction in the level of mRNA. Expression of tyrosine kinases varied independently, and individual lines contained various combinations of these enzymes. Our findings are consistent with an increased overall expression of these putative growth factor receptors during melanoma development.
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PMID:Novel and known protein tyrosine kinases and their abnormal expression in human melanoma. 822 28

A new cancer cell line (KKP) was established from an ascitic effusion of an advanced gastric adenocarcinoma, intestinal type. The line has been maintained in continuous monolayer culture with a doubling time of 48 hours for more than 2 years. KKP cells, whose ultrastructural features are presented, showed an aneuploid DNA content, a modal number of 53 chromosomes, and the presence of one double minute chromosome. The karyotype showed trisomies of chromosomes 7, 12, 13, and 14, tetrasomy of chromosome 18, a reciprocal translocation [t(1;20)(q21;p11.2)], and a [t(4;?)] rearrangement. No amplification or rearrangements were evident in the c-MYC, c-ERB B2, H-RAS, INT-2, HST-1, c-MOS, and K-RAS genes, whereas somatic rearrangements were present in the sequences corresponding to c-MET and cyclin E genes by Southern blotting analysis. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of P53 and RB genes did not reveal alterations or point mutations in the SSCP pattern of conformers. The chemosensitivity pattern assay of the KKP cell line indicated that it was sensitive to cisplatin, etoposide, and doxorubicin and resistant to 4'-hydroperoxycyclophosphamide. The clinical history of the patient from whom the cell line was derived is reported and compared with the results observed in the cell line in vitro. High levels of the tumor-associated antigens CEA (carcinoembryonic antigen) and CA19-9 were evident in the KKP cytosol, whereas the KKP spent culture medium maintained the same low levels of CEA and CA 19-9 found in the patient's serum. This new cell line may represent a useful tool for studying the biology of gastric cancer and for planning new therapeutic approaches.
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PMID:Molecular genetics and in vitro sensitivity of a new human cell line, KKP, from a gastric adenocarcinoma. 968 29

We are investigating novel, non-transcriptionally mediated mechanisms that may contribute to the differentiative effects of oestrogen in developing forebrain neurons. Recent findings in the cerebral cortex document that 17 alpha- and 17 beta-oestradiol elicit rapid and sustained activation of the Ras-Raf-MAP kinase cascade, a major growth factor signalling pathway. Using oestrogen receptor (ER) alpha knockout (ERKO) mice, we addressed the identity of the receptor mediating activation of the MAP kinase cascade. 17 beta-oestradiol increased B-Raf activity and MEK-dependent ERK phosphorylation in explants of wild-type and ERKO cerebral cortex. Although neither the ER alpha-selective ligand, 16 alpha-iodo-17 beta-oestradiol (16 alpha-IE2) nor the ER beta-selective ligand, genistein, elicited ERK phosphorylation, as little as 0.1 nM 17 beta-oestradiol did so. Moreover, 16 alpha-IE2 acted as an inhibitory modulator of ERK activation, and the ER antagonist ICI 182 780 blocked oestradiol action only in wild-type cultures. These data suggest that neither ER alpha nor ER beta mediate activation of the MAP kinase cascade. A putative, novel, oestradiol-sensitive and ICI 182 780-insensitive receptor, designated ER-X may, rather, be involved. Association of ER-X with flotillin, the neuronal homologue of the caveolar protein, caveolin, places ER-X within plasma membrane caveolae and supports the hypothesis that a membrane-associated ER may mediate rapid oestrogen activation of the MAP kinase cascade.
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PMID:Novel sites and mechanisms of oestrogen action in the brain. 1096 2

We showed previously in neocortical explants, derived from developing wild-type and estrogen receptor (ER)-alpha gene-disrupted (ERKO) mice, that both 17alpha- and 17beta-estradiol elicit the rapid and sustained phosphorylation and activation of the mitogen-activated protein kinase (MAPK) isoforms, the extracellular signal-regulated kinases ERK1 and ERK2. We proposed that the ER mediating activation of the MAPK cascade, a signaling pathway important for cell division, neuronal differentiation, and neuronal survival in the developing brain, is neither ER-alpha nor ER-beta but a novel, plasma membrane-associated, putative ER with unique properties. The data presented here provide further evidence that points strongly to the existence of a high-affinity, saturable, 3H-estradiol binding site (K(d), approximately 1.6 nm) in the plasma membrane. Unlike neocortical ER-alpha, which is intranuclear and developmentally regulated, and neocortical ER-beta, which is intranuclear and expressed throughout life, this functional, plasma membrane-associated ER, which we have designated "ER-X," is enriched in caveolar-like microdomains (CLMs) of postnatal, but not adult, wild-type and ERKO neocortical and uterine plasma membranes. We show further that ER-X is functionally distinct from ER-alpha and ER-beta, and that, like ER-alpha, it is re-expressed in the adult brain, after ischemic stroke injury. We also confirmed in a cell-free system that ER-alpha is an inhibitory regulator of ERK activation, as we showed previously in neocortical cultures. Association with CLM complexes positions ER-X uniquely to interact rapidly with kinases of the MAPK cascade and other signaling pathways, providing a novel mechanism for mediation of the influences of estrogen on neuronal differentiation, survival, and plasticity.
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PMID:ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. 1235 13

The ability of estrogen to rapidly initiate a variety of signal transduction cascades is increasingly recognized as playing an important role in a number of tissue-specific transcriptional actions of the hormone. In vivo, estrogen rapidly elicits phosphorylation of cAMP response element-binding protein (CREB). We have previously shown that both ER alpha and ER beta are capable of activating the MAPK pathway in response to a low dose of 17beta-estradiol. In the present study, the ability of estrogen to act through both ER alpha and ER beta to increase CREB phosphorylation was evaluated in an immortalized hippocampal cell line stably expressing either receptor. Estrogen treatment promoted rapid CREB phosphorylation, reaching a maximum by 15 min. This activation is completely blocked by the antiestrogen ICI 182,780, suggesting an estrogen receptor-dependent mechanism. The addition of the mitogen/ERK kinase-1 inhibitor, PD98059, also blocked the ability of estrogen to signal to CREB phosphorylation. Estrogen also caused an increase in p90Rsk activity, a critical mediator of MAPK effects. Surprisingly, blockade of the protein kinase A pathway in cells treated with estrogen did not affect estrogen-mediated CREB phosphorylation. Thus, MAPK and p90Rsk appear to be the primary mediators of estrogen-induced gene transcription through ER alpha and ER beta.
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PMID:Estrogen activation of cyclic adenosine 5'-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. 1258 59

The differential expression pattern of estrogen receptor alpha (ER-alpha), estrogen receptor beta (ER-beta) and their co-activator/co-repressor proteins is thought to modulate estrogenic action and to be present already during the early stages of tumorigenesis. It has therefore been postulated that certain co-activator and co-repressor proteins contribute to the development of breast cancer. There are some reports providing information on gene amplification and mRNA over-expression of certain co-factors in breast cancer, but to date there is only limited knowledge about their respective protein expressions. The aim of this study was to examine the expression of four steroid receptor co-activators (steroid receptor co-activator 1 (SRC-1), transcription intermediary factor 2 (TIF 2), protein 300 kDa/CREB binding protein (p300/CBP), amplified in breast cancer 1 (AIB1)), and of the co-repressor nuclear receptor co-repressor (NCoR), in malignant breast tissues and in matching normal breast biopsies of the same individuals. Protein expression was analyzed by immunohistochemistry and was compared to prognostic parameters such as lymph node involvement, tumor grading and receptor status. All members of the co-regulatory protein family were detected in both, benign and matching malignant tissue samples, except for AIB1, which was found to be expressed exclusively in malignant epithelium. AIB1 was preferentially present in carcinomas with high tumor grade (r = 0.48, p = 0.014), and was co-expressed with p300/CBP (r = 0.54, p = 0.006). TIF 2 correlated significantly to nodal status (r = 0.46, p = 0.025). Furthermore, protein levels of ER-beta p300/CBP and AIB1 were higher in invasive ductal carcinomas than in normal mammary tissue. The tumoral ER-alpha protein expression was significantly correlated with that of PgR (r = 0.61, p = 0.001) and NCoR (r = 0.4, p = 0.043), whereas ER-beta expression was associated with SRC-1 (r = 0.68, p < or = .001), TIF 2 (r = 0.64, p = 0.001) and NCoR (r = 0.48, p = 0.014) protein levels in malignant specimens. In our hands, 20% of ER-beta positive tumors did not express ER-alpha protein, thereby suggesting that a substantial fraction of ER-beta positive tumors is falsely considered to be 'estrogen receptor negative' if only ER-alpha specific antibodies are employed in the histological assessment of the ER status.
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PMID:Expression of sex steroid receptors and their co-factors in normal and malignant breast tissue: AIB1 is a carcinoma-specific co-activator. 1272 19

Genistein, a component of soy, has been reported to protect against spontaneously developing prostate tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. This is consistent with reports showing that Asians eating a diet high in soy have reduced incidence of clinically manifested prostate cancer. In order to understand the mechanism of action of genistein, we have investigated the expression of androgen and estrogen receptors, four growth factor receptors that signal via tyrosine protein kinases, and specific growth factor proteins in the dorsolateral prostates of TRAMP mice fed 250 mg genistein/kg diet, starting at 5 weeks of age. These analyses were carried out at 12 weeks, prior to the development of solid tumors, allowing us to readily investigate cell proliferation and biomarkers in premalignant tissue. Cell proliferation, AR, ER-alpha, EGFR, ErbB2, EGF, IGF-1R, IGF-1, VEGFR2, ERKs-1 and 2 proteins and TGF-alpha mRNA, but not ER-beta and VEGF, were significantly increased in prostates of TRAMP compared to C57BL/6 mice. Genistein in the diet significantly down-regulated cell proliferation, EGFR, IGF-1R, ERK-1 and ERK-2, but not AR, ER-alpha, ER-beta, ErbB2, EGF, TGF-alpha, IGF-1, VEGF and VEGFR in prostates of TRAMP mice. Serum testosterone and dihydrotestosterone concentrations were not significantly different in C57BL/6 or TRAMP male mice fed control or genistein-containing diets. The up-regulation of sex steroid receptors and multiple growth signaling pathways in TRAMP mice supports the concept of multiple dysregulation contributing to carcinogenesis. Down-regulation of the tyrosine kinase regulated proteins, EGFR and IGF-1R, and of the downstream mitogen-activated protein kinases, ERK-1 and 2, with genistein in the diet provides a possible mechanism for prostate cancer chemoprevention.
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PMID:Genistein alters growth factor signaling in transgenic prostate model (TRAMP). 1514 38

The capability of 17beta-estradiol (E2) to induce the non-genomic activities of its receptors (ER alpha and ER beta) and to evoke different signaling pathways committed to the regulation of cell proliferation has been analyzed in different cell cancer lines containing transfected (HeLa) or endogenous (HepG2, DLD1) ER alpha or ER beta. In these cell lines, E2 induced different effects on cell growth/apoptosis in dependence of ER isoforms present. The E2-ER alpha complex rapidly activated multiple signal transduction pathways (i.e., ERK/MAPK, PI3K/AKT) committed to both cell cycle progression and apoptotic cascade prevention. On the other hand, the E2-ER beta complex induced the rapid and persistent phosphorylation of p38/MAPK which, in turn, was involved in caspase-3 activation and cleavage of poly(ADP-ribose)polymerase, driving cells into the apoptotic cycle. In addition, the E2-ER beta complex did not activate any of the E2-ER alpha-activated signal molecules involved in cell growth. Taken together, these results demonstrate the ability of ER beta isoform to activate specific signal transduction pathways starting from plasma membrane that may justify the effect of E2 in inducing cell proliferation or apoptosis in cancer cells. In particular this hormone promotes cell survival through ER alpha non-genomic signaling and cell death through ER beta non-genomic signaling.
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PMID:Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling. 1538 27

The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-alpha and ER-beta. Although ER-alpha has been well characterized, the role of ER-beta as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-alpha, ER-beta and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n=150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of beta-oestradiol and tamoxifen was assessed using Western blotting (n=14). Oestrogen receptor-beta protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P=0.0008 and P<0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (P<0.0001 and P<0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to beta-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-beta and SRC-1 was inversely associated (P=0.0001). The association of ER-beta protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.
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PMID:Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer. 1547 68


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