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)

Human Aurora-A is related to a protein kinase originally identified by its close homology to Ipl1p from Saccharomyces cerevisiae and aurora from Drosophila melanogaster, which are key regulators of the structure and function of the mitotic spindle. We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)-ubiquitin-proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.
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PMID:Degradation of human Aurora-A protein kinase is mediated by hCdh1. 1202 18

C-mos is a cytoplasmic upstream activator of the mitogen-activating protein kinase pathway with serine-threonine kinase activity. It plays a well established and vital role in oocyte maturation by participating in metaphase II arrest and meiotic asymmetric division, but little is known about its function in somatic cells. Recently, we observed overexpressed c-mos in a portion of non-small cell lung carcinomas (NSCLCS). In particular, c-mos immunoreactivity was detected in tumor cell nuclei in addition to its expected cytoplasmic localization, and c-mos overexpression was associated with chromosomal instability among other findings. To verify our earlier observations and to clarify further the role of c-mos in NSCLCS, we examined its distribution by both light and electron microscopy. We detected c-mos in the cytoplasm and/or nucleus of a portion of tumor cells and fibroblasts. In particular, granular immunoreactivity was observed in the cytoplasm closely associated with the rough endoplasmic reticulum. Nuclear staining was confirmed and was often found near the nuclear membrane, as well as in some large multilobular, possibly aneuploid, nuclei. C-mos positivity was also found in the nuclei of tumor cells undergoing apoptosis. Furthermore, c-mos was detected in areas with diminished vascularization. It should be noted that nuclear staining was found at the ultrastructural level more extensively than at the light microscope study. This suggests a masking effect by the hematoxylin nuclear counterstain.
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PMID:Immunohistochemical localization of c-mos at the light and electron microscope level in non-small cell lung carcinomas. 1208 89

The CNS neurotoxic effects of lead (Pb) are well documented; however, the molecular toxicity targets have not been clearly delineated. Astroglial cells, which are the most abundant cells in the brain and provide critical support to the neurons, are known to accumulate Pb. Although NO generated by inducible NO synthase (iNOS) in glial cells has been associated with many neurotoxic events, it can also serve to protect by modulating blood flow, increase antimicrobial and tumoricidal activities, and promote immune responses following injury or insult. The present investigations were designed to test the hypothesis that Pb exposure may perturb cytokine signal transduction pathways leading to NO production by astroglial cells. Pretreatment with Pb acetate (500 nM-10 microM) attenuated the generation of NO in a concentration-dependent manner up to 90%, and suppressed iNOS protein expression, as well as interfered with the homeostatic functions of calcium in the cytokine-induced NO signal transduction pathway. In addition, pretreatment with staurosporine, a serine-threonine kinase inhibitor, or KT5720, a specific protein kinase A inhibitor (PKA), inhibited cytokine-induced NO production in a concentration-dependent manner with IC(50) values of 26.3 and 346.7 nM, respectively. Therefore, Pb may impede events within the PKA signal transduction pathway; although, based on results from a gel shift assay, Pb does not directly affect PKA enzyme activity. Taken together, these results suggest the possibility that the suppressive effect of Pb acetate on cytokine-induced NO production in glial cells may be implicated in the neurophysiologic changes noted following occupational or environmental exposure to Pb.
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PMID:The in vitro effects of Pb acetate on NO production by C6 glial cells. 1220 16

Sporothrix schenckii is a pathogenic fungus that undergoes a dimorphic transition from yeast to mycelium in response to environmental conditions such as cell density, temperature, and calcium. We identified a homolog of the Pho85 cyclin-dependent kinase (Cdk) that mediates cellular responses to environmental conditions in other organisms. By Western blot, three proteins containing the PSTAIRE motif, which characterize the cyclin-dependent protein kinases, were identified in S. schenckii. The gene encoding a Pho85 homolog, PhoSs, was identified and sequenced. The phoSs gene consists of 990bp, contains one intron, and encodes a protein of 306 amino acids. The S. schenckii Pho85 homolog shares features with Cdks, including the PSTAIRE motif, an ATP binding domain, and a serine-threonine kinase domain. By quantitative competitive RT-PCR, expression of the phoSs gene was found to decrease 30-fold during the yeast to mycelium transition. The addition of extracellular calcium accelerated the dimorphic transition and restored phoSs expression. These findings suggest PhoSs may participate in the control of the yeast to mycelium transition in S. schenckii.
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PMID:Expression of a Pho85 cyclin-dependent kinase is repressed during the dimorphic transition in Sporothrix schenckii. 1222 88

Aurora-A is a serine/threonine protein kinase that plays a role in cell-cycle regulation. The activity of this kinase has been shown to be required for regulating multiple stages of mitotic progression in somatic cells. In this study, the changes in aurora-;A expression were revealed in mouse oocytes using Western blotting. The subcellular localization of aurora-A during oocyte meiotic maturation, fertilization, and early cleavages as well as after antibody microinjection or microtubule assembly perturbance was studied with confocal microscopy. The quantity of aurora-A protein was high in the germinal vesicle (GV) and metaphase II (MII) oocytes and remained stable during other meiotic maturation stages. Aurora-A concentrated in the GV before meiosis resumption, in the pronuclei of fertilized eggs, and in the nuclei of early embryo blastomeres. Aurora-A was localized to the spindle poles of the meiotic spindle from the metaphase I (MI) stage to metaphase II stage. During early embryo development, aurora-A was found in association with the mitotic spindle poles. Aurora-A was not found in the spindle region when colchicine or staurosporine was used to inhibit microtubule organization, while it accumulated as several dots in the cytoplasm after taxol treatment. Aurora-A antibody microinjection decreased the rate of germinal vesicle breakdown (GVBD) and distorted MI spindle organization. Our results indicate that aurora-A is a critical regulator of cell-cycle progression and microtubule organization during mouse oocyte meiotic maturation, fertilization, and early embryo cleavage.
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PMID:Aurora-A is a critical regulator of microtubule assembly and nuclear activity in mouse oocytes, fertilized eggs, and early embryos. 1469 13

We used differential display PCR to identify hepatic genes responsive to handling stress and genes that differ in expression between populations of a fish, Fundulus heteroclitus, from different thermal environments. Despite substantial inter-individual variation, we cloned 20 putatively stress-regulated bands from Northern fish, 10 of which had high similarity to genes of known function. We selected five of these genes for further analysis based on their known roles in the stress response. Three of these genes (glucokinase, serine-threonine kinase 10 and cRAF) were confirmed as stress-responsive using real-time PCR. These genes increased in expression in response to a 7-day chronic stress protocol in fish from the Southern population of F. heteroclitus, but did not change significantly in fish from the Northern population. These three genes also differed in expression between populations in control fish, suggesting a link between the response to chronic stress and inter-population differences in gene expression in unstressed laboratory-acclimated fish. Two genes that did not respond to stress (glycogen synthase kinase and warm acclimation-related protein (WAP)) also differed between populations. Expression of WAP was eight-fold higher in Southern than in Northern fish, consistent with a previously suggested role for this gene in thermal acclimation or adaptation in fish.
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PMID:Variation in gene expression in response to stress in two populations of Fundulus heteroclitus. 1472 Jun 6

HIPK2 is a member of a novel family of nuclear serine-threonine kinases identified through their ability to interact with the Nkx-1.2 homeoprotein. The physiological role of these kinases is largely unknown, but we have recently reported on the involvement of HIPK2 in the induction of apoptosis of tumor cells after UV stress through p53 phosphorylation and transcriptional activation. Here, we demonstrate that the chemotherapeutic drug cisplatin increases HIPK2 protein expression and its kinase activity, and that HIPK2 is involved in cisplatin-dependent apoptosis. Indeed, induction of HIPK2 and of cell death by cisplatin are efficiently inhibited by the serine-threonine kinase inhibitor SB203580 or the transduction of HIPK2-specific RNA-interfering molecules. HIPK2 gene silencing efficiently reduces the p53-mediated transcriptional activation of apoptotic gene promoters as well as apoptotic cell death after treatment with cisplatin. These findings, along with the involvement of p53 phosphorylation at serine 46 (Ser46) in the transcriptional activation of apoptotic gene promoters, suggest a critical role for HIPK2 in triggering p53-dependent apoptosis in response to the antineoplastic drug cisplatin.
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PMID:Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. 1472 69

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine-threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA's actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches.
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PMID:Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases. 1501 27

Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and is regulated by numerous factors including polyamines. Although the exact roles of polyamines in apoptotic pathway are still unclear, inhibition of polyamine synthesis promotes the resistance of intestinal epithelial cells to apoptosis. Akt is a serine-threonine kinase that has been established as an important intracellular signaling in regulating cell survival. The current studies test the hypothesis that polyamines are involved in the control of Akt activity in normal intestinal epithelial cells (IEC-6 line) and that activated Akt mediates suppression of apoptosis following polyamine depletion. Depletion of cellular polyamines by alpha-difluoromethylornithine induced levels of phosphorylated Akt and increased Akt kinase activity, although it had no effect on expression of total Akt, pERK, p38, and Bcl-2 proteins. This activated Akt was associated with both decreased levels of active caspase-3 and increased resistance to tumor necrosis factor-alpha/cycloheximide-induced apoptosis. Inactivation of Akt by either treatment with LY294002 or ectopic expression of a dominant negative Akt mutant (DNMAkt) not only enhanced the caspase-3 activation in polyamine-deficient cells but also prevented the increased resistance to tumor necrosis factor-alpha/cycloheximide-induced apoptosis. Phosphorylation of glycogen synthase kinase-3, a downstream target of Akt, was also increased in alpha-difluoromethylornithine-treated cells, which was prevented by inactivation of Akt by LY294002 or DNMAkt overexpression. These results indicate that polyamine depletion induces the Akt activation mediating suppression of apoptosis via inhibition of caspase-3 in normal intestinal epithelial cells.
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PMID:Akt kinase activation blocks apoptosis in intestinal epithelial cells by inhibiting caspase-3 after polyamine depletion. 1502 23

Aurora-A protein kinase, which is the product of an oncogene, is required for the assembly of a functional mitotic apparatus and the regulation of cell ploidy. Overexpression of Aurora-A in tumour cells has been correlated with cancer susceptibility and poor prognosis. Aurora-A activity is required for the recruitment of CDK1-cyclin B1 to the centrosome prior to its activation and the commitment of the cell to mitosis. In this report, we demonstrate that the CDC25B phosphatase, an activator of cyclin dependent kinases at mitosis, is phosphorylated both in vitro and in vivo by Aurora-A on serine 353 and that this phosphorylated form of CDC25B is located at the centrosome during mitosis. Knockdown experiments by RNAi confirm that the centrosome phosphorylation of CDC25B on S353 depends on Aurora-A kinase. Microinjection of antibodies against phosphorylated S353 results in a mitotic delay whilst overexpression of a S353 phosphomimetic mutant enhances the mitotic inducing effect of CDC25B. Our results demonstrate that Aurora-A phosphorylates CDC25B in vivo at the centrosome during mitosis. This phosphorylation might locally participate in the control of the onset of mitosis. These findings re-emphasise the role of the centrosome as a functional integrator of the pathways contributing to the triggering of mitosis.
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PMID:Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition. 1512 71


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