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)

Repeated administration of psychostimulants like methamphetamine and cocaine induce behavioral sensitization, which is recognized as an animal model for dependence and psychoses. Many previous studies have proved two major cascades play a crucial roles for molecular mechanisms underling sensitization. The first one is activation of D1 dopamine receptors by robust increase of dopamine release, followed by activation of adenylyl cyclase, increase of cyclic AMP, activation of protein kinase A (PKA) and phosphorylation of proteins by PKA. The second one is activation of NMDA receptor by enhanced release of glutamine, followed by increased intracellular Ca2+ concentration, formation of Ca2+/calmodulin complex, and phosphorylation of several proteins such as calcineurin, CaM-K II and nitric oxide synthase. Recent advanced findings on sensitization mechanisms were reviewed from three different aspects: 1) Studies using knockout mice offered quite amazing findings that D1DA-receptor-lacking mice or dopamine-transporter-lacking mice can develop sensitization and dependence, which were not consistent with the previously established hypotheses based on behavioral pharmacology. In addition, those data showed the important roles of vesicular monoamine transporter 2, 5HT1B receptors and delta FosB. 2) Research on neural-plasticity-related sensitization revealed the involvement of several molecules such as tissue plasminogen activator, arc (activity-regulated, cytoskeleton-associated), synaptophysin and stathmin. Increased expression of these genes may participate in the rearrangement of neural networks with synaptogenesis and expansion of dendrites 3) Trials to discover novel-genes-involved sensitization phenomenon using differential display or subtraction cloning found some candidate genes, mrt-1, NAC-1 and CART. Although in these areas are still in progress, accumulating findings will elucidate the details of the molecular mechanism of behavioral sensitization and dependence.
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PMID:[Advanced findings on the molecular mechanisms for behavioral sensitization to psychostimulants]. 1123 97

In the central nervous system, stressful conditions can easily cause the oxidation of lipoprotein particles, followed by the oxidative modification of apolipoproteins such as apolipoprotein E (apoE) and the production of free radicals and aldehydes. We have confirmed that oxidized very-low-density lipoprotein (VLDL) inhibits the proliferation, viability and differentiation of neuronal PC12 cells leading to cell death. The cells internalized intact apoE, but did not internalize oxidized apoE. The phosphorylation of stathmin and various mitogen-activated protein (MAP) kinases including extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) was examined in PC12 cells exposed to native and oxidized VLDL, H(2)O(2) (which generates free radicals), and 4-hydroxy-2-nonenal (HNE) (an aldehyde). Oxidized VLDL and H(2)O(2) reduced stathmin phosphorylation while HNE increased it, suggesting that oxidized VLDL and H(2)O(2) stimulated similar signal transduction pathways. Based on the results, free radicals, but not aldehydes may play a major role in the neuronal cell death induced by lipoprotein oxidation. Furthermore, the phosphorylation status of MAP kinases indicated that the activation of the JNK cascade might be required for neuronal cell death.
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PMID:Electrophoretic studies on the phosphorylation of stathmin and mitogen-activated protein kinases in neuronal cell death induced by oxidized very-low-density lipoprotein with apolipoprotein E. 1198 45

cDNA microarrays and two-dimensional gel-electrophoresis in combination with mass spectrometry, were used to screen alterations in mRNA and protein levels, respectively, in cerebral cortex of MK-801-treated rats. The rats were divided in two groups; group 1 (short-term treated) and group 2 (long-term treated). In group 1, four genes were up-regulated and five down-regulated. In group 2, seven genes were up-regulated and six down-regulated. In group 1, the levels of one protein was increased and eight proteins reduced. In group 2, the levels of two proteins were increased and four proteins reduced. Several of the altered genes (casein kinase 2, glutamic acid decarboxylase, synaptotagmin, gamma aminobutyric acid [GABA] transporter, creatine kinase, and cytochrome c oxidase) and proteins (superoxide dismutase, hsp 60, hsp 72 and gamma-enolase) have previously been connected to schizophrenia. Alterations of the genes (microglobulin, c-jun proto-oncogene, 40S ribosomal protein S19, adenosine diphosphate (ADP)-ribosylation factors, platelet-derived growth factor, fructose-bisphophate aldolase A, and myelin proteolipid) and the proteins (stathmin, H+-transp. Adenosine triphosphate (ATP) synthase, pyruvate dehydrogenase, beta-actin and alpha-enolase), have not, to our knowledge, earlier been implicated in schizophrenia pathology. Overall, these results with a combined approach of genomics and proteomics add to the validity of subchronic N-methyl-D-aspartate (NMDA)-receptor antagonist treatment as an animal model of schizophrenia.
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PMID:Comparative genome- and proteome analysis of cerebral cortex from MK-801-treated rats. 1254 8

Molecular mechanisms in the development of drug abuse and dependence were reviewed by taking behavioral sensitization induced by psychostimulants like amphetamines and cocaine as a typical example. Behavioral sensitization is characterized by three main features, progressive quantitative and qualitative changes in responsiveness to the drug, very long-lastingness, and development of vulnerability to other drugs and nonspecific physical and psychological stressors, in other words, cross-sensitization. These serial changes in response to the drug during abuse must result from plastic changes in the brains of abusers. As to subcellular neurochemical mechanisms of sensitization, the activation of three main cascades is indispensable, 1) D1 dopamine (DA) receptors/PKA/phospho-34Thr-DARPP-32/PP-1 cascade activated by psychostimulant-induced enhancement of DA release in the accumbens, 2) NMDA receptors and CaM-KII activated by enhanced release of glutamate, 3) activation of MAP kinase cascade by BDNF and beta 1 subunit of G protein. These, in turn, activate several transcription factors, including delta-Fos B, and affect transcription and translation of 4th or later messengers. Finally, these result in the rearrangement of neural networks, where the tone of the A10 dopamine pathway from the ventral tegmentum area to the accumbens is strengthened, and regulation by glutamatergic afferents from the frontal cortex, amygdala and hippocampus shifts into abnormal positive regulation. As amphetamines increase expression of some plasticity-related genes (e.g. synaptophysin, stathmin and arc), synaptogenesis, neuritic sprouting and elongation must develop during behavioral sensitization. These plastic changes with structural modification of neural networks in the CNS during drug abuse could induce and reinforce psychological dependence and susceptibility to drug-induced psychoses, which become increasingly intractable.
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PMID:[Molecular biology of drug dependence and behavioral sensitization]. 1264 9

Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). The cDNA-oligoarray analysis and reverse transcription-PCR verification indicated common changes in gene expression in methionine-dependent cell lines to include up-regulation/induction of cyclin D1, mitotic arrest deficient (MAD)1, p21, growth arrest and DNA-damage-inducible (GADD)45 alpha, GADD45 gamma, GADD34, breast cancer (BRCA)1, 14-3-3sigma, B-cell CLL/lymphoma (BCL)1, transforming growth factor (TGF)-beta, TGF-beta-induced early response (TIEG), SMAD5, SMAD7, SMAD2, insulin-like growth factor binding protein (IGFBP7), IGF-R2, vascular endothelial growth factor (VEGF), TNF-related apoptosis-inducing ligand (TRAIL), TNF-alpha converting enzyme (TACE), TRAIL receptor (TRAIL-R)2, TNFR-related death receptor (DR)6, TRAF interacting protein (I-TRAF), IL-6, MDA7, IL-1B convertase (ICE)-gamma, delta and epsilon, IRF1, IRF5, IRF7, interferon (IFN)-gamma and receptor components, ISG15, p65-NF-kappaB, JUN-B, positive cofactor (PC)4, C/ERB-beta, inositol triphosphate receptor I, and methionine adenosyltransferase II. On the other hand, cyclins A1, A2, B1 and B2, cell division cycle (CDC)2 and its kinase, CDC25 A and B, budding uninhibited by benzimidazoles (BUB)1 and 3, MAD2, CDC28 protein kinase (CKS)1 and 2, neuroepithelial cell transforming gene (NET)1, activator of S-phase kinase (ASK), CDC14B phosphatase, BCL2, TGF-beta activated kinase (TAK)1, TAB1, c-FOS, DNA topoisomerase II, DNA polymerase alpha, dihydrofolate reductase, thymidine kinase, stathmin, and MAP4 were down-regulated. In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45alpha and gamma in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of MDA7 and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress down-regulated the highly active phosphatidylinositol 3'-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor kappaB under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.
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PMID:Modulation of gene expression in human central nervous system tumors under methionine deprivation-induced stress. 1549 78

Emerging evidences suggest that cyclin-dependent kinase inhibitors (CKIs) can regulate cellular functions other than cell cycle progression, such as differentiation and migration. Here, we report that cytoplasmic expression of p27(kip1) affects microtubule (MT) stability following cell adhesion on extracellular matrix (ECM) constituents. This p27(kip1) activity is due to its ability to bind and impair the function of the MT-destabilizing protein stathmin. Accordingly, upregulation of p27(kip1) or downregulation of stathmin expression results in the inhibition of mesenchymal cell motility. Moreover, high stathmin and low cytoplasmic p27(kip1) expression correlate with the metastatic phenotype of human sarcomas in vivo. This study provides a functional link between proliferation and invasion of tumor cells based on diverse activities of p27(kip1) in different subcellular compartments.
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PMID:p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion. 1565 49

Members of the stathmin-like protein family depolymerize microtubules (MTs), probably due to the ability of each stathmin monomer to bind two tubulin heterodimers in a complex (T(2)S complex). SCG10, a member of this family, is localized in the growth cone of neurons. It has four identified sites of serine phosphorylation (S50, S63, S73, and S97). Of these, S50 and S97 are phosphorylated by cAMP-dependent protein kinase, an enzyme involved in growth cone guidance. When the equivalent sites in stathmins are phosphorylated, they lose their ability to depolymerize MTs. We investigated the specific role of the two cAMP-dependent protein kinase (PKA) phosphorylation sites in SCG10. A mutant of SCG10 phosphorylated only on S50 retained the ability to depolymerize MTs, but SCG10 phosphorylated on S97 or on both S50 and S97 lost MT-depolymerizing activity. Surface plasmon resonance studies revealed that the phosphorylation of SCG10 at these sites reduced the tubulin heterodimer binding, mainly due to a reduced rate of association. In particular, compared to the two other phosphorylated forms, SCG10 phosphorylated at S50 had a significantly smaller dissociation constant for the binding of the first tubulin heterodimer and larger association and dissociation rate constants for the binding of the second heterodimer. This indicates that the phosphorylation of S50 compensates for the effect of phosphorylation at other sites by modulating T2S complex formation. Furthermore, these results suggest that S50-P maintains MT-depolymerizing activity, which indicates that the biological functions of phosphorylation at S50 and S97 are different.
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PMID:Role of Ser50 phosphorylation in SCG10 regulation of microtubule depolymerization. 1582 89

Accumulated evidence suggests that actin and microtubule regulating proteins contribute to neuronal structural dynamics, which subsequently affect neuronal plasticity. SCG10 is a neuronal-specific stathmin protein with microtubule destabilizing activity that is affected by multiple phosphorylation, at least in vitro. SCG10 has four major phosphorylation sites: Ser50 and Ser97 targeted by protein kinase A (PKA), and Ser62 and Ser73 targeted by mitogen-activated protein kinase (MAPK). To explore the potential roles of site-specific phosphorylation in physiological models, we developed phosphorylation site-specific antibodies and examined the SCG10 status in primary cultured hippocampal neurons and tissues. Although SCG10 is concentrated in growth cones and the Golgi apparatus in primary cultured neurons, the phosphorylated form was also detected in both regions, suggesting that MT dynamics within the growth cone may be regulated by protein phosphorylation. In the adult hippocampus, an intense stimulus such as kainate treatment induced a rapid phosphorylation of Ser73 within 15 min that was sustained for at least 60 min. This response was mediated through the N-methyl D-aspartic acid (NMDA) receptor and was ablated by the antagonist MK-801. The MAPK enzyme Erk2 was simultaneously activated along a similar time course to SCG10, suggesting that Erk2 may directly phosphorylate Ser73. These results demonstrate that changes in the phosphorylation status of SCG10 in vivo, dependent upon neural activity and/or plasticity, could affect the microtubule dynamics in neuronal dendrites.
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PMID:Site-specific phosphorylation of SCG10 in neuronal plasticity: role of Ser73 phosphorylation by N-methyl D-aspartic acid receptor activation in rat hippocampus. 1636 89

The tumor suppressor gene CDKN1B encodes for a 27-kDa cyclin-dependent kinase inhibitory protein, p27Kip1, which together with its well-established role in the inhibition of cell proliferation, displays additional activities in the control of gene transcription and cell motility. p27Kip1 thus represents a good candidate for a gene therapy approach, especially in those cancers refractory to the conventional therapies, like human glioblastoma. Here, we show that overexpression of p27Kip1 in glioblastoma cell lines induced cell cycle arrest and inhibition of cell motility through extracellular matrix substrates. The use of adenoviral vectors in the treatment of glioblastoma in vivo showed that p27Kip1 was able to block not only cancer cell growth but also local invasion and tumor-induced neoangiogenesis. The latter effect was due to the ability of p27 to impair both endothelial cell growth and motility, thus preventing proper vessel formation in the tumor. The block of neoangiogenesis depended on cytoplasmic p27Kip1 antimigratory activity and was linked to its ability to bind to and inhibit the microtubule-destabilizing protein stathmin. Our work provides the first evidence that a successful p27Kip1-based gene therapy is linked to tumor microenvironment modification, thus opening new perspectives to the use of gene therapy approaches for the treatment of refractory cancers.
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PMID:p27Kip1 expression inhibits glioblastoma growth, invasion, and tumor-induced neoangiogenesis. 1848 4

Recently we showed Lupeol, a triterpene, found in fruits and vegetables inhibits the growth of tumors originated from human androgen-sensitive prostate cancer (CaP) cells and decreases the serum-PSA levels in a mouse model. Here, we provide evidence that Lupeol inhibits the growth of androgen-sensitive as well as androgen-insensitive CaP cells by inducing G2/M cell cycle arrest without exhibiting any toxicity to normal human prostate epithelial cells (PrEC) at the doses at which it kills cancer cells. We observed that Lupeol treatment to LNCaP and DU145 cells resulted in a dose-dependent (i) decrease in the protein levels of Cyclins-A, -B1, -D1, -D2, -E2, cyclin-dependent kinase (cdk)-2 and (ii) increase in the protein level of CDK-inhibitor p21. Since G2/M cell cycle phase is regulated by microtubule assembly, we investigated effect of Lupeol on microtubule assembly, its regulation and down-stream targets in CaP cells. Lupeol treatment significantly modulated the level of (i) microtubule components alpha-tubulin and beta-tubulin, (ii) microtubule-regulatory protein stathmin, and (iii) microtubule-regulatory down-stream target/pro-survival protein survivin. Lupeol treatment also decreased the level of anti-apoptotic protein cFLIP. Finally, Lupeol was observed to significantly decrease the transcriptional activation of survivin and cFLIP genes in CaP cells. We conclude that the Lupeol-induced growth inhibition of CaP cells is a net outcome of simultaneous effects on stathmin, cFLIP, and survivin which results in the disruption of microtubule assembly. We suggest that Lupeol alone or as an adjuvant to other microtubule agents could be developed as a potential agent for the treatment of human CaP.
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PMID:Lupeol triterpene, a novel diet-based microtubule targeting agent: disrupts survivin/cFLIP activation in prostate cancer cells. 1968 15


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