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)

Polypeptide drugs are generally short-lived species in circulation. In this study, we have covalently linked seven moieties of 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) to the amino groups of human interferon-alpha2. The derivative thus obtained (FMS(7)-IFN-alpha2) has approximately 4% the biological potency and 33 +/- 4% the receptor binding capacity of the native cytokine. Upon incubation, FMS(7)-IFN-alpha2 undergoes time-dependent spontaneous hydrolysis, generating active interferon with t(1/2) values of 24 +/- 2 h at pH 8.5 and 98 +/- 10 h at pH 7.4. When native IFN-alpha2 is intravenously administered to mice, circulating antiviral activity is maintained for a short duration and then declines with t(1/2) = 4 +/- 0.5 h, reaching undetectable values at approximately 18 h after administration. With intravenously administered FMS(7)-IFN-alpha2, there is a lag period of 2 h, followed by a progressive elevation in circulating antiviral-active protein, which peaked at 20 h and declined with t(1/2) = 35 +/- 4 h. FMS(7)-IFN-alpha2 is resistant to alpha-chymotrypsin digest and to proteolytic inactivation by human serum proteases in vitro. We have thus introduced here an inactive IFN-alpha2 derivative, which is resistant to in situ inactivation and has the capability of slowly reverting to the native active protein at physiological conditions in vivo and in vitro. Having these attributes, FMS(7)-IFN-alpha2 maintains prolonged circulating antiviral activity in mice, exceeding 7-8 times the activity of intravenously administered native cytokine.
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PMID:Prolonging the half-life of human interferon-alpha 2 in circulation: Design, preparation, and analysis of (2-sulfo-9-fluorenylmethoxycarbonyl)7- interferon-alpha 2. 1115 19

The expression of vascular endothelial growth factor mRNA and protein is regulated by a number of agents including growth factors, cytokines, and phorbol esters. Here we report that vascular endothelial growth factor is able to increase its own level in cultured human dermal microvascular endothelial cells. Accumulation of vascular endothelial growth factor mRNA and polypeptide can be detected as early as 4 h after addition of vascular endothelial growth factor to the cell culture medium. The autocrine action of vascular endothelial growth factor appears to be mediated by the KDR receptor. The increase of its own message by vascular endothelial growth factor is blocked by the transcription inhibitor actinomycin D. Transient transfection experiments performed with human dermal microvascular endothelial cells and using a 3.2 kb human vascular endothelial growth factor promoter fragment showed that vascular endothelial growth factor auto-induction can be mimicked at the promoter level. This indicates that the observed vascular endothelial growth factor mRNA increase after vascular endothelial growth factor treatment is occurring at the level of transcription. Furthermore, vascular endothelial growth factor auto-induction is inhibited by PD 098059, showing that phosphorylation events, catalyzed by mitogen activated protein kinases, are a prerequisite for the vascular endothelial growth factor effect. Examination of extracellular signal-regulated kinase and c-Jun N-terminal protein kinase catalytic activities showed that both enzymes have to be activated to mediate the vascular endothelial growth factor signal. Our data demonstrate for the first time the existence of an autocrine loop for vascular endothelial growth factor in endothelial cells. Most probably this represents an amplification mechanism for the action of vascular endothelial growth factor in the microvascularization process.
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PMID:An autocrine loop mediates expression of vascular endothelial growth factor in human dermal microvascular endothelial cells. 1128 18

Autocrine and paracrine signaling leading to stimulation of tumor cell growth is a common theme in human cancers. In addition to polypeptide growth factors such as EGF family members which signal through receptor tyrosine kinases, accumulating evidence supports the autocrine and paracrine involvement of specific neuropeptides with defined physiologic actions as neurotransmitters and gut hormones in lung, gastric, colorectal, pancreatic and prostatic cancers. These neuropeptides, including gastrin-releasing peptide, neuromedin B, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric G proteins. Studies with human small cell lung cancer (SCLC) cells support a requirement for balanced signaling through G(q) and G(12/13) proteins leading to intracellular Ca2+ mobilization, PKC activation and regulation of the ERK and JNK MAP kinase pathways. While specific neuropeptide antagonists offer promise for interrupting the single neuropeptide autocrine systems operating in pancreatic and prostatic cancers, SCLC is exemplified by multiple, redundant neuropeptide autocrine systems such that tumor growth cannot be inhibited with a single specific antagonist. However, a novel class of neuropeptide derivatives based on the substance P sequence have been defined that exhibit broad specificity for neuropeptide receptors and induce apoptosis in SCLC by functioning as biased agonists that stimulate discordant signal transduction. Thus, interruption of autocrine and paracrine neuropeptide signaling with specific antagonists or broad-spectrum biased agonists offer promising new therapeutic approaches to the treatment of human cancers.
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PMID:Autocrine and paracrine signaling through neuropeptide receptors in human cancer. 1131 3

Previous findings suggest that both the Tat polypeptide encoded by HIV-1 and Tat-derived peptides can induce angiogenesis via activation of the KDR receptor for Vascular Endothelial Growth Factor (VEGF). We identified 20 amino acids and 12 amino acid peptides corresponding to the cysteine-rich and basic domains of HIV-1 Tat which inhibited (125)I-VEGF(165) binding to KDR and neuropilin-1 (NP-1) receptors in endothelial cells. Cysteine-rich and basic Tat peptides inhibited VEGF-induced ERK activation and mitogenesis in endothelial cells, and inhibited angiogenesis in vitro at concentrations similar to those which inhibited VEGF receptor binding. These peptides also inhibited proliferation, angiogenesis, and ERK activation induced by basic fibroblast growth factor with similar potency and efficacy. Surprisingly, we found that both cysteine-rich and basic domain Tat peptides strikingly induced apoptosis in endothelial cells, independent of their effects on VEGF and bFGF. Furthermore, we found no evidence for direct biological effects of recombinant Tat on VEGF receptor binding, ERK activation, endothelial cell survival, or mitogenesis. These findings demonstrate novel properties of Tat-derived peptides and indicate that their major effect in endothelial cells is apoptosis independent of specific inhibition of VEGF receptor activation.
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PMID:Cysteine-rich and basic domain HIV-1 Tat peptides inhibit angiogenesis and induce endothelial cell apoptosis. 1132 25

The four ERBB receptors and their multiple polypeptide ligands are differentially expressed during development of the mouse mammary gland. Profiles suggest that ERBB1/EGF receptor (EGFR)4 and ERBB2/Neu are required during ductal morphogenesis, whereas the Neuregulin (NRG) receptors, ERBB3 and ERBB4, are preferentially expressed through alveolar morphogenesis and lactation. Consistent with these profiles, recent gene knockouts established that EGFR and its ligand, Amphiregulin (AR), are essential for ductal morphogenesis in the adolescent mouse and likely provide the required epithelial-stromal signal. In contrast, the phenotypes of transgenic mice expressing dominant negative ERBB2 and ERBB4 proteins suggest that these receptors differentially act to promote or maintain alveolar differentiation. This view of ERBB action provides a conceptual framework for future testing using more sophisticated conditional knockout models. New or existing transgenic mice are also being used to better understand the contributions of ERBB receptors and ligands to mammary tumorigenesis, as well as to more closely mimic the human disease. Recent studies have focused on defining molecular events in neoplastic progression, and in the case of ERBB2/Neu, the requirement for ERBB heterodimerization partners as well as the relative importance of gene amplification versus gene mutation. Collectively, these recent studies establish that normal development and homeostasis of the mammary gland is critically dependent on regulated ERBB signaling. They also illustrate the value of animal models in deciphering roles for the complex ERBB network in this dynamic tissue.
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PMID:Regulation of mouse mammary gland development and tumorigenesis by the ERBB signaling network. 1146 54

Heregulin (HRG) is one of the groups of polypeptide growth factors that activate the erbB-2 receptor via induction of heterodimerization with erbB-3 and erbB-4 receptors. The biological effects of HRG have been extensively studied. The vast majority of the reports indicate that HRG induces cell growth in breast cancer cells expressing normal levels of erbB-2 and growth inhibition and apoptosis in cells over-expressing erbB-2. However, the mechanism by which HRG promotes cell growth inhibition and apoptosis is still unknown. Previously we reported that constitutive expression of HRG in an erbB-2-overexpressing cell line (SKBr-3) induced growth arrest and apoptosis. We also demonstrated that constitutive expression of HRG promoted a marked morphological change, G2/M delay of the cell cycle, and DNA fragmentation. In this study, we demonstrate the mechanism by which HRG induces these cellular effects. The doubling time of the SK/HRG cells increased in relation to the level of HRG expression, and the level of HRG expression dictates the morphological change of the cells as well as their ability to grow or not grow in an anchorage-independent manner. We demonstrate that these effects are accompanied by downregulation of both erbB-2 and erbB-3 receptors at the transcriptional and translational levels and that down-regulation of the erbB-receptors results in reduced receptor tyrosine phosphorylation. The decrease in erbB-receptor phosphorylation in turn results in a marked reduction of ERK activity and a significant increase in JNK activity. Consequently, overexpression of HRG promoted the expression of PEA3, an Ets nuclear transcription factor. Taken together, our data demonstrate that the cellular effects induced by constitutive expression of HRG in SKBr-3 cells are correlated with the level of HRG expression. This is a first report demonstrating that HRG induction of apoptosis is directly correlated with decreased MAPK activity, increased JNK activity resulting in upregulation of PEA3 and down-regulation of the erbB-2 receptor. Overall, these data provide important clues regarding the mechanism and downstream molecules involved in HRG induction of apoptosis that can be used as targets for therapeutic prevention.
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PMID:Signaling molecules implicated in heregulin induction of growth arrest and apoptosis. 1160 34

Heregulin-beta1 (HRG) is a regulatory polypeptide having several distinct biological effects in mammary epithelial cells. To address the hypothesis that HRG selectively regulates gene expression, we performed differential display screening using cells grown in the presence or absence of HRG. One cDNA clone upregulated by HRG was identical to human calnexin, a protein with molecular chaperone function. This is the first demonstration of the regulation of calnexin mRNA and protein expression by a physiologically relevant polypeptide factor in human breast cancer cells. HRG stimulation also caused a rapid redistribution of calnexin from vesicle-like structures in the cell cytoplasm to the perinuclear area and to the cell membrane. Furthermore, HRG induced colocalization and physical interaction of calnexin with the HER2 growth factor receptor. Finally, calnexin protein levels were increased in progressive stages of human breast cancer. These findings suggest that stimulation of calnexin expression by HRG may constitute a mechanism of protein redistribution and facilitate downstream signaling events in growth-factor-activated cells.
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PMID:Growth factor regulation of the molecular chaperone calnexin. 1172 8

It is estimated that up to one in five individuals develop pituitary gland tumors. Despite the common occurrence of these tumors, the pathogenetic mechanisms underlying their development remain largely unknown. We report the identification of a novel pituitary tumor-derived, N-terminally truncated isoform of FGF receptor-4 (ptd-FGFR4). The corresponding mRNA results from alternative transcription initiation and encodes a polypeptide that lacks a signal peptide and the first two extracellular Ig-like domains. ptd-FGFR4 has a distinctive cytoplasmic residence, is constitutively phosphorylated, and is transforming in vitro and in vivo. Here we show that targeted expression of ptd-FGFR4, but not FGFR4, results in pituitary tumors that morphologically recapitulate the human disease.
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PMID:Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. 2623 43

In the small, free-living amoeba Acanthamoeba castellanii, rRNA transcription requires, in addition to RNA polymerase I, a single DNA-binding factor, transcription initiation factor IB (TIF-IB). TIF-IB is a multimeric protein that contains TATA-binding protein (TBP) and four TBP-associated factors that are specific for polymerase I transcription. TIF-IB is required for accurate and promoter-specific initiation of rRNA transcription, recruiting and positioning the polymerase on the start site by protein-protein interaction. In A. castellanii, partially purified TIF-IB can form a persistent complex with the ribosomal DNA (rDNA) promoter while homogeneous TIF-IB cannot. An additional factor, TIF-IE, is required along with homogeneous TIF-IB for the formation of a stable complex on the rDNA core promoter. We show that TIF-IE by itself, however, does not bind to the rDNA promoter and thus differs in its mechanism from the upstream binding factor and upstream activating factor, which carry out similar complex-stabilizing functions in vertebrates and yeast, respectively. In addition to its presence in impure TIF-IB, TIF-IE is found in highly purified fractions of polymerase I, with which it associates. Renaturation of polypeptides excised from sodium dodecyl sulfate-polyacrylamide gels showed that a 141-kDa polypeptide possesses all the known activities of TIF-IE.
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PMID:A novel RNA polymerase I transcription initiation factor, TIF-IE, commits rRNA genes by interaction with TIF-IB, not by DNA binding. 1178 52

P19 embryonic carcinoma (EC) cells are one of the simplest systems for analyzing the neuronal differentiation. To identify the membrane-associated molecules on the neuronal cells involved in the early neuronal differentiation in mice, we generated two monoclonal antibodies, SKY-1 and SKY-2, by immunizing rats with a membrane fraction of the neuronally committed P19 EC cells as an antigen. SKY-1 and SKY-2 recognized the carbohydrate moiety of a 90 kDa protein (RANDAM-1) and the polypeptide core of a 40 kDa protein (RANDAM-2), respectively. In the P19 EC cells, the expression of RANDAM-1 was colocalized to a part of Nestin-positive cells, whereas that of RANDAM-2 was observed in most Nestin-positive cells as well as beta-III-tubulin positive neurons. In the embryonic and adult brain of mice, RANDAM-1 was expressed at embryonic day 8.5 (E8.5), and the localization of antigen was restricted on the neuroepithelium and choroid plexus. The RANDAM-2 expression commenced at E6.0, and the antigen was distributed not only on the neuroepithelium of embryonic brain but on the neurons of adult brain. Collectively, it was concluded that RANDAM-1 is a stage specific antigen to express on the neural stem cells, and RANDAM-2 is constitutively expressed on both the neural stem cells and differentiated neuronal cells in mouse central nervous system (CNS).
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PMID:Identification of neuronal cell lineage-specific molecules in the neuronal differentiation of P19 EC cells and mouse central nervous system. 1189 72


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