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)

As the biochemical detection of bovine papillomavirus type 4 E5 is problematic, a fusion form of E5 and the green fluorescent protein (GFP-E5) was constructed and its characteristics were examined. GFP-E5 was detected in cells by autofluorescence and immunoblotting. Like wild-type (wt) E5, GFP-E5 localized in the endomembranes and permitted anchorage-independent (AI) growth. However, unlike wt E5, cells expressing GFP-E5 became quiescent in low serum and failed to sustain expression of cyclins D1 and to inactivate retinoblastoma protein (pRb). The normal anchorage requirement for cyclin D1 and cyclin A expression was abolished in cells expressing wt E5 or GFP-E5, residual extracellular signal-regulated kinase (ERK 1/2) activity was not required to sustain cyclin D1 and cyclin A expression in suspension and deregulation of cyclin A-cyclin-dependent kinase (CDK) activity was sufficient to account for AI growth of cells expressing E5. Constitutive upregulation of the CDK inhibitor p27(KIP1), characteristic of cells expressing wt E5, was not observed in those expressing GFP-E5; therefore, p27(KIP1) deregulation is not required for E5-mediated AI growth.
J Gen Virol 2004 Dec
PMID:Cyclin A expression and growth in suspension can be uncoupled from p27 deregulation and extracellular signal-regulated kinase activity in cells transformed by bovine papillomavirus type 4 E5. 1555 31

Hepatitis C virus non-structural NS5A protein inhibits epidermal growth factor (EGF)-stimulated activation of the Ras-ERK mitogen-activated protein kinase pathway at a point upstream of Ras activation. To determine the mechanism of this inhibition, the events occurring between the EGF receptor and Ras in Huh-7 cells harbouring the HCV subgenomic replicon were investigated. It was shown that, following EGF stimulation, these cells exhibited decreased EGF receptor tyrosine phosphorylation, aberrant recruitment of the adaptor proteins ShcA and Grb2 to the EGF receptor, reduced phosphorylation of ShcA and reduced Ras activation in comparison with control cells. These data are consistent with effects of NS5A and/or other components of the replicon on multiple events occurring upstream of Ras.
J Gen Virol 2005 Apr
PMID:Perturbation of epidermal growth factor receptor complex formation and Ras signalling in cells harbouring the hepatitis C virus subgenomic replicon. 1578 96

Pituitary, a master gland of neuroendocrine system, secretes hormones that orchestrate many physiological processes, under the regulation of multiple signaling pathways. To investigate the genes involved in hormones expression of human pituitary, homemade cDNA microarray containing 14,800 human genes/ESTs were used to profile the gene expression in both fetal and adult pituitaries. Seven hundred and twelve known genes changed over 2-fold between the both tissues. Of which, 23 genes were changed with hormones expression in aging were confirmed by RT-PCR, not only the known regulators such as Pit1, GATA4, ESRRA, GABA-A, and EMK, but also LOC55884, DUSP3, PNN, and RCL, which had not been reported to be involved in the hormones expression. Correspondingly, the mRNAs of GH, PRL, POMC, TSH-beta, FSH-beta, and LH-beta, was increased as much as 6- to 20-fold in adult pituitary than those in fetal pituitary, by real-time quantitative RT-PCR assay. In addition, the mRNAs of signaling pathways, such as cAMP-PKA-CREB, PI3K-Akt, and PKA-ERK were further investigated. Of them, it was only cAMP-PKA-CREB pathway, but not PI3K-Akt and PKA-ERK have the same expressing pattern as hormones. It suggested that cDNA microarray is highly advantages to profile the differential expressed genes that were involved in hormones expression of human pituitary, but it might ignore some responding proteins regulated posttranscriptionally.
Gen Comp Endocrinol 2005 Sep 01
PMID:cDNA microarray reveals signaling pathways involved in hormones expression of human pituitary. 1589 16

We propose a new mechanism to explain autoinhibition of the epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases based on a structural model that postulates both their juxtamembrane and protein tyrosine kinase domains bind electrostatically to acidic lipids in the plasma membrane, restricting access of the kinase domain to substrate tyrosines. Ligand-induced dimerization promotes partial trans autophosphorylation of ErbB1, leading to a rapid rise in intracellular [Ca(2+)] that can activate calmodulin. We postulate the Ca(2+)/calmodulin complex binds rapidly to residues 645--660 of the juxtamembrane domain, reversing its net charge from +8 to -8 and repelling it from the negatively charged inner leaflet of the membrane. The repulsion has two consequences: it releases electrostatically sequestered phosphatidylinositol 4,5-bisphosphate (PIP(2)), and it disengages the kinase domain from the membrane, allowing it to become fully active and phosphorylate an adjacent ErbB molecule or other substrate. We tested various aspects of the model by measuring ErbB juxtamembrane peptide binding to phospholipid vesicles using both a centrifugation assay and fluorescence correlation spectroscopy; analyzing the kinetics of interactions between ErbB peptides, membranes, and Ca(2+)/calmodulin using fluorescence stop flow; assessing ErbB1 activation in Cos1 cells; measuring fluorescence resonance energy transfer between ErbB peptides and PIP(2); and making theoretical electrostatic calculations on atomic models of membranes and ErbB juxtamembrane and kinase domains.
J Gen Physiol 2005 Jul
PMID:An electrostatic engine model for autoinhibition and activation of the epidermal growth factor receptor (EGFR/ErbB) family. 1595 74

Dysregulation of receptor tyrosine kinase (RTK) activity has been implicated in the progression of a variety of human leukemias. Most notably, mutations and chromosomal translocations affecting regulation of tyrosine kinase activity in the Kit receptor, the Flt3 receptor, and the PDGFbeta/FGF1 receptors have been demonstrated in mast cell leukemia, acute myeloid leukemia (AML), and chronic myelogenous leukemias (CML), respectively. In addition, critical but non-overlapping roles for the Ron and Kit receptor tyrosine kinases in the progression of animal models of erythroleukemia have been demonstrated [Persons, D., Paulson, R., Loyd, M., Herley, M., Bodner, S., Bernstein, A., Correll, P. and Ney, P., 1999. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat. Gen. 23, 159-165.; Subramanian, A., Teal, H.E., Correll, P.H. and Paulson, R.F., 2005. Resistance to friend virus-induced erythroleukemia in W/Wv mice is caused by a spleen-specific defect which results in a severe reduction in target cells and a lack of Sf-Stk expression. J. Virol. 79 (23), 14586-14594.]. The various classes of RTKs implicated in the progression of leukemia have been recently reviewed [Reilly, J., 2003. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev. 17 (4), 241-248.]. Here, we will discuss the mechanism by which alterations in these receptors result in transformation of hematopoietic cells, in the context of what is known about the molecular regulation of RTK activity, with a focus on our recent studies of the Ron receptor tyrosine kinase.
 ...
PMID:Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies. 1652 73

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. KSHV infection of cells produces both latent and lytic cycles of infection. In vivo, the virus is found predominantly in the latent state. In vitro, a lytic infection can be induced in KSHV-infected cells by treating with phorbol ester (TPA). However, the exact signalling events that lead to the reactivation of KSHV lytic infection are still elusive. Here, a role is demonstrated for B-Raf/MEK/ERK signalling in TPA-induced reactivation of KSHV latent infection. Inhibiting MEK/ERK signalling by using MEK-specific inhibitors decreased expression of the TPA-induced KSHV lytic-cycle gene ORF8. Transfection of BCBL-1 cells with B-Raf small interfering RNA inhibited TPA-induced KSHV lytic infection significantly. Additionally, overexpression of MEK1 induced a lytic cycle of KSHV infection in BCBL-1 cells. The significance of these findings in understanding the biology of KSHV-associated pathogenesis is discussed.
J Gen Virol 2006 May
PMID:Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency. 1660 14

Chronic intermittent high altitude (IHA) hypoxia results in long-term adaptation protecting the heart against acute ischemia/reperfusion injury; however, molecular mechanisms of this phenomenon are not completely elucidated so far. The present study was aimed at investigation of a modulating effect of IHA hypoxia on the expression and/or activation of selected regulatory proteins, with particular emphasis on differential responses in the right ventricle (RV) and left ventricle (LV). Adult male Wistar rats were exposed to IHA hypoxia of 7000 m simulated in a hypobaric chamber (8 h/day, 25 exposures), and protein contents and activities in myocardial fractions were determined by Western blot analysis. In markedly hypertrophic RV of hypoxic rats, gelatinolytic activity of MMP-2 and protein levels of carbonic anhydrase IX (a marker of hypoxia) were significantly enhanced. Study of mitogen-activated protein kinases (MAPKs) revealed no differences in the contents of total p38-MAPK in both ventricles between the IHA and normoxic control rats, whereas activation of p38-MAPK was decreased in the RV and moderately increased in the LV of IHA rats as compared to controls. Extracellular signal regulated kinase-2 (ERK-2) was partially up-regulated in the RV of IHA rats, and, in addition, expression of acidic fibroblast growth factor (aFGF), a potential activator of ERK cascade, was also significantly increased. In contrast, expression of ERKs in the LV as well as their activities in both ventricles, were not affected by IHA hypoxia. Differential effects of IHA hypoxia on c-Jun-N-terminal protein kinases (JNKs) in the RV and LV were also observed. As compared with the controls, total content of JNKs was increased in the RV of the IHA rats, while expression of JNKs in the LV was down-regulated. IHA hypoxia changed neither total levels of Akt kinase in both RV and LV, nor Akt kinase activity in the RV. However, increased levels of activated phospho-Akt kinase were found in the LV of IHA rats. The results demonstrate that adaptation of rat hearts to chronic IHA hypoxia is associated with disctinct changes in the levels and/or activation of several regulatory proteins in two ventricles. The latter could be attributed to both myocardial remodeling and cardioprotection induced by chronic hypoxia.
Gen Physiol Biophys 2006 Mar
PMID:Changes in the expression and/or activation of regulatory proteins in rat hearts adapted to chronic hypoxia. 1671 73

To gain further insight into the role of cortisol in fish innate immune responses, we cloned and sequenced a 2592bp cDNA from sea bass (Dicentrarchus labrax) peritoneal leukocytes (PCLs) encoding a glucocorticoid receptor (DlGR1). The deduced aminoacid sequence displayed that DlGR1 belong to a multigenic family of steroid hormone receptors, and exhibited high homology (80%) to the Burton's mouth breeder (Haplochromis burtoni) HbGR1. The DlGR1 functional domains presented homologies with those of several vertebrate species. In situ hybridization assay revealed that DlGR1 was expressed in macrophages and neutrophils from the peritoneal cavity. Since in a previous paper, sea bass PCL chemiluminescence response (CL) has been related to increased respiratory burst of phagocytes stimulated with zymosan, PCLs, pre-incubated in vitro with cortisol at various concentrations, were assayed for their CL response. Dose-dependent cortisol inhibitory effects, and significant competitive activity of a low concentration of mifepristone (RU486), a glucocorticoid-receptor blocker, supported that cortisol-GR interaction was involved in modulating CL response via a genomic pathway. Results also indicated that cortisol could be effective through an additional not-genomic way, and showed that high doses of RU486 exerted an inhibitory effect on PCL chemiluminescence activity.
Gen Comp Endocrinol 2007 Jan 01
PMID:Peritoneal cavity phagocytes from the teleost sea bass express a glucocorticoid receptor (cloned and sequenced) involved in genomic modulation of the in vitro chemiluminescence response to zymosan. 1698 19

Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely distributed neuropeptide that has various different functions in the nervous system and in non-neural tissues. Little is known about the effects of PACAP in endothelial cells. The aim of the present study was to investigate the effects of PACAP on endothelial cell survival and apoptotic signaling pathways under oxidative stress. Mouse hemangioendothelioma (EOMA) cells were exposed to 0.5mM H(2)O(2) which resulted in a marked reduction of cell viability and a parallel increase of apoptotic cells assessed by MTT test and flow cytometry. Co-incubation with 20nM PACAP1-38 increased cell viability and reduced the percentage of apoptotic cells. Flow cytometry analysis showed that oxidative stress reduced the phosphorylation of the anti-apoptotic ERK and increased the phosphorylation of the pro-apoptotic JNK and p38 MAP kinases. PACAP1-38 treatment ameliorated these changes: levels of phospho-ERK were elevated and those of phospho-JNK and p38 were decreased. All these effects were abolished by simultaneous treatment with the PACAP antagonist PACAP6-38. In summary, our results show that PACAP effectively protects endothelial cells against the apoptosis-inducing effects of oxidative stress.
Gen Comp Endocrinol
PMID:Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis. 1727 Jan 84

Pretreatment with diazoxide, mitochondrial K(ATP) channel opener, was found to protect the rat heart against ischemia/reperfusion injury. Our aim was also to characterize the effects of diazoxide on the alterations of regulatory myocardial proteins, on mitochondrial ultrastructure, integrity and induction of apoptotic responses. Isolated rat hearts were Langendorff perfused and subjected to index ischemia (II) induced by 25 min global ischemia and 35 min reperfusion. In diazoxide- treated hearts, diazoxide (50 micromol/l) was applied 15 min before II. The levels and activation of specific proteins were determined using specific antibodies, activities of matrix metalloproteinases by zymography using gelatin as a substrate. The ultrastructure of mitochondria was investigated by electron microscopy of ultrathin sections of mitochondrial fractions embedded in Epon812. In rat hearts pretreated with diazoxide we found better recovery of contractile function after II. Electron microscopy studies revealed that application of diazoxide was connected with better preservation of mitochondrial integrity at basal conditions and after II in comparison to control hearts. Ischemia induced activation of caspase-3 as well as decrease of mitochondria-associated Bcl-2 levels but diazoxide treatment did not significantly influence these changes. On the other hand, diazoxide pretreatment reduced the cytosolic levels of pro-apoptotic Bax protein. Western blot analysis revealed that application of diazoxide increased activation of both ERK-1 and ERK-2 as compared with control hearts. ERK-2 activities were also higher in diazoxide-treated hearts after II when compared to control hearts. Moreover, application of diazoxide inhibited the activities of tissue matrix metalloproteinases (MMP-2). The results suggest that the cardioprotection mediated by diazoxide in rats is associated with preservation of mitochondrial integrity and function. The effect of diazoxide on ERK pathway points to the involvement of this signaling cascade in diazoxide-mediated adaptive responses of myocardium to ischemia.
Gen Physiol Biophys 2007 Jun
PMID:Changes in rat myocardium associated with modulation of ischemic tolerance by diazoxide. 1766 May 80


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