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)

The involvement of metabotropic glutamate receptor group II (mGluRII) in the induction of long-term depression (LTD) was investigated in the medial perforant path of the rat dentate gyrus, a region with a very high density of mGluRII. Perfusion of either of two potent mGluRII agonists, (2S,1R,2R,3R)-2-(2S, 1'R, 2'R, 3'R)-2 (2' 3'-dicarboxycyclopropyl)glycine (DCG-IV) or (+)-2- aminobicyclo[3.1.0]hexane-2-6-dicarboxylic acid (LY354740) induced a reversible inhibition of the field EPSP followed, upon washout of the agonist, by LTD. The reversible inhibition was associated with a change in paired pulse depression, indicating an underlying presynaptic reduction in the probability of transmitter release, whereas the LTD was not associated with a change in paired pulse depression, indicating either a presynaptic reduction in the number of active release sites, or a postsynaptic change. Further evidence that the DCG-IV-induced LTD was generated by activation of mGluRII was the finding that the mGluRII antagonist (RS)-alpha-methylserine-O-phosphate monophenylphosphoryl ester (MSOPPE) prevented the induction of the LTD induced by DCG-IV. The DCG-IV-induced LTD showed mutual occlusion with LFS-induced LTD. The generation of the agonist-induced LTD required, in part, activation of N-methyl-D-aspartate receptors (NMDAR), as LTD induction was partially blocked in the presence of the NMDAR antagonist D-2-amino-5-phosphonopentanoate (AP5). Evidence for involvement of protein kinase C (PKC) and protein kinase (PKA) in the induction of LTD by activation of mGluRII was obtained by showing an inhibition of the DCG-IV-induced LTD by the PKC inhibitors Ro-31-8220 and bisindolylmaleimide I, and also by the PKA inhibitor H-89. The study demonstrates that activation of mGluRII induces LTD via activation the PKA and PKC pathways in the medial perforant path of the dentate gyrus.
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PMID:Activation of mGluRII induces LTD via activation of protein kinase A and protein kinase C in the dentate gyrus of the hippocampus in vitro. 1019

The involvement of protein kinases A and C in the induction of low frequency stimulation-induced long-term depression (LTD) in the medial perforant path of the dentate gyrus in vitro has been studied using the selective PKA inhibitors H-89 and KT 5720 and PKC inhibitors Bisindolylmaleimide and Ro-31-8220. The PKC inhibitors Bisindolylmaleimide I and Ro-31-8220 and the PKA inhibitors H-89 and KT5720 all partially inhibited LTD induction. However, the presence of both a PKC and a PKA inhibitor was necessary to completely block LTD induction. The induction of long-term potentiation was not blocked by the inhibitors. It is suggested that the induction of LTD by LFS involves activation of PKC and PKA following activation of group I and group II metabotropic glutamate receptors (mGluR).
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PMID:Role of protein kinases A and C in the induction of mGluR-dependent long-term depression in the medial perforant path of the rat dentate gyrus in vitro. 1055 40

The integrity of the DNA damage response pathway is essential for prevention of neoplastic transformation. Several proteins involved in this pathway including p53, BRCA1, and ATM are frequently mutated in human cancer. Checkpoint kinase 2 (Chk2) is a DNA damage-activated protein kinase that lies downstream of ATM in this pathway. Recently, heterozygous germline mutations in Chk2 have been identified in a subset of patients with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype, suggesting that Chk2 is a tumor suppressor gene. In this study, we have reported the biochemical characterization of the four tumor-associated Chk2 mutants. Two of the reported Chk2 mutations identified in Li-Fraumeni syndrome result in loss of Chk2 kinase activity. Whereas one mutation within the Chk2 forkhead homology-associated (FHA) domain, R145W, retains some basal kinase activity, this mutant cannot be phosphorylated at an ATM-dependent phosphorylation site (Thr-68) and cannot be activated following gamma radiation. Wild-type Chk2 exists mainly in a protein complex of M(r) approximately 200,000 whereas the R145W mutant forms a larger, presumably inactive complex in the cell. The other FHA domain mutant, I157T, behaves as wild-type Chk2 in all the assays used here. Because the FHA domain is involved in protein-protein interactions, this mutation may affect associations of Chk2 with other proteins. Additionally, we have shown that Chk2 can also be inactivated by down-regulation of its expression in cancer cells. Thus, Chk2 may be inactivated by multiple mechanisms in the cell.
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PMID:Characterization of tumor-associated Chk2 mutations. 1105 50

The CHK2 gene encodes a protein kinase that is important for the regulation of cell cycle arrest after DNA damage. CHK2 acts downstream of ataxia teleangiecstasia mutated (ATM), modulates the function of p53 and may help mediate cell cycle arrest at G2/M by phosphorylation of Cdc25C. Recently, the human homolog of the checkpoint kinase Cds1 (CHK2) has been suggested to be a tumor suppressor gene. Heterozygous germline mutations have been reported in Li-Fraumeni syndrome (LFS), a highly penetrant familial cancer phenotype, and in sporadic colon cancer. LFS is associated with the development of lymphoid malignancies, especially childhood ALL. Therefore, we analyzed the DNA from 143 lymphoid malignancies to determine whether they had mutations of the CHK2 gene. The 14 exons of CHK2 were studied by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and sequencing of aberrantly migrating bands. One missense mutation changing serine to phenylalanine (codon 428) in an evolutionarily highly conserved domain was found in a non-Hodgkin's aggressive lymphoma. Another point mutation in the non-coding region was identified in one of adult T-cell leukemias (ATL) samples. This result suggests that mutation of the CHK2 gene may rarely be involved in the development of selected lymphomas.
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PMID:Analysis of the CHK2 gene in lymphoid malignancies. 1169 18

Photodynamic therapy (PDT) is a cancer therapy in which a photosensitizer selectively accumulates in tumor cells and is subsequently activated by light of a specific wavelength. The activation of the photosensitizer leads to cytotoxic photoproducts that result in tumor regression. PDT can lead to several cellular responses including cell cycle arrest, necrosis, and apoptosis, as well as trigger many signaling pathways. It has been suggested that extracellular signal-activated protein kinases (ERKs), one subfamily of mitogen-activated protein kinases, play a crucial role in the cellular response to radiation therapy and chemotherapy. However, the role of ERKs in the cell survival after PDT is less clear. We have examined the response of the extracellular signal-regulated kinase ERK1/2 in PDT-resistant (LFS087) and PDT-sensitive (GM38A) cells after Photofrin-mediated PDT. ERK1/2 activity was induced rapidly in both cell types after PDT. The PDT-induced ERK1/2 activity was transient in GM38A cells and by 3 h had returned to a level significant lower than basal levels, whereas the induction of ERK1/2 was sustained in LFS087 cells and lasted for at least 11 h. Blocking of the sustained ERK activity with PD98059, an inhibitor of mitogen-activated protein/ERK kinase, significantly decreased cell survival of LFS087 after PDT. PDT also induced the expression of mitogen-activated protein kinase phosphatase, MKP-1, but reduced Raf-1 protein levels in both cell types. In GM38A cells, the substantially induced levels of MKP-1 correlated with the transient activation of ERK1/2 by PDT, and both basal and induced levels of MKP-1 were substantially greater in GM38 compared with Li Fraumeni syndrome cells. These observations suggest that sustained ERK1/2 activation protects cells from Photofrin-mediated phototoxicity and that the duration of ERK1/2 activation is regulated by MKP-1. In addition, the activation of ERK1/2 by Photofrin-mediated PDT is Raf-1 independent.
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PMID:Sustained activation of the extracellular signal-regulated kinase pathway protects cells from photofrin-mediated photodynamic therapy. 1235 64

Chk2 is a serine/threonine protein kinase found mutated in certain hereditary and sporadic cancers. Ionizing radiation (IR) activates the kinase activity of Chk2 in a phosphorylation-dependent manner. ATM phosphorylates Chk2 on threonine 68, which promotes oligomerization and phosphorylation on threonines 383 and 387 within the activation loop of the catalytic domain. In this study, threonines 68, 383, and 387 were confirmed as sites of Chk2 phosphorylation both in vitro and in vivo. In addition, serine 516 was identified as a novel IR-inducible phosphorylation site in vivo and as a site of autophosphorylation in vitro. Interestingly, Chk2 was capable of autoactivation in the absence of IR when overproduced in bacteria, in 293 cells, and in murine embryonic fibroblasts lacking Chk2. A kinase-inactive mutant of Chk2 was phosphorylated on T68 and T383/T387 but not on S516 in cells containing Chk2 and on T68 but not T383/T387 or S516 in cells lacking Chk2. This establishes a dependency on Chk2 kinase activity for phosphorylation of T383/T387 and S516 but not for T68 in vivo. We demonstrate that T68 phosphorylation is regulated by kinases in addition to ATM and Chk2. Taken together, our data indicate that autophosphorylation of Chk2 can occur both in cis and in trans and suggest that oligomerization may regulate Chk2 activation by promoting these cis- and trans-phosphorylation events. The importance of oligomerization is underscored by the observation that substitution of isoleucine for threonine at position 157, a mutation found in a subset of patients with Li-Fraumeni syndrome, impairs both Chk2 oligomerization and autophosphorylation.
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PMID:Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. 1280 7

Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl) glycine (DCGIV; 5 microM), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 microM), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 microM) was combined with a cell-permeant PKA inhibitor H-89 (10 microM), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 microM), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 microM), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6-cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 microM), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity.
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PMID:Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses. 1632 19

Activity-dependent changes in synaptic efficacy are thought to be the key cellular mechanism for the formation and storage of both explicit and implicit memory. Different patterns of stimulation can elicit different changes in the efficiency on excitatory synaptic transmission. Here, we examined the synaptic changes in the amygdala of adult mice produced by low-frequency stimulation (1 Hz, 15 min, LFS). We first compared the synaptic changes induced by LFS in three different synaptic pathways of amygdala: cortical-lateral amygdala, thalamic-lateral amygdala, and lateral-basolateral amygdala pathways. We find that the plastic changes induced by LFS are different between synaptic pathways. Low-frequency stimulation selectively elicits a slow onset and protein synthesis-dependent late-phase LTP in the cortical-lateral amygdala pathway, but not in the thalamic-lateral or lateral-basolateral pathways. We next analyzed LTP induced by LFS in the cortical-lateral amygdala pathway and found that three PKA-coupling neurotransmitter receptors are involved: 5-HT4, Dopamine D1, and beta-adrenergic receptors. Antagonists of these receptors block the LFS L-LTP, but the effects of agonists of these receptors are clearly different. These results indicate that the threshold for the induction of LFS L-LTP is different among these pathways and that the maintenance of LFS L-LTP requires a cross-talk among multiple neurotransmitters.
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PMID:Low-frequency stimulation induces a pathway-specific late phase of LTP in the amygdala that is mediated by PKA and dependent on protein synthesis. 1762 8

Previously, we found that in the lateral amygdala (LA) of the mouse, WIN55,212-2 decreases both glutamatergic and GABAergic synaptic transmission via activation of the cannabinoid receptor type 1 (CB1), yet produces an overall reduction of neuronal excitability. This suggests that the effects on excitatory transmission override those on inhibitory transmission. Here we show that CB1 activation by WIN55,212-2 and Delta(9)-THC inhibits long-term depression (LTD) of basal synaptic transmission in the LA, induced by low-frequency stimulation (LFS; 900 pulses/1 Hz). The CB1 agonist WIN55,212-2 blocked LTD via G(i/o) proteins, activation of inwardly rectifying K+ channels (K(ir)s), inhibition of the adenylate cyclase-protein kinase A (PKA) pathway, and PKA-dependent inhibition of voltage-gated N-type Ca2+ channels (N-type VGCCs). Interestingly, WIN55,212-2 effects on LTD were abolished in CB1 knock-out mice (CB1-KO), and in conditional mutants lacking CB1 expression only in GABAergic interneurons, but were still present in mutants lacking CB1 in principal forebrain neurons. LTD induction per se was unaffected by the CB1 antagonist SR141716A and was normally expressed in CB1-KO as well as in both conditional CB1 mutants. Our data demonstrate that activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the LA. These findings suggest that CB1 expressed on either glutamatergic or GABAergic neurons play a differential role in the control of synaptic transmission and plasticity.
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PMID:Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala. 1832 69

Approximately 50% of sporadic human tumors harbor somatic mutations in the p53 gene locus, while germ line mutations confer a high familial risk and are associated with Li-Fraumeni Syndrome patients. The p53 tumor suppressor protein is often referred to as the "guardian of the genome" since its response to DNA-damage or checkpoint failure gives rise to a series of anti-proliferative responses. One of the most important functions of p53 is its ability to induce apoptosis, while disruption of this route can promote tumor progression and chemo resistance. Besides its ability to promote apoptosis through transcription dependent mechanisms, p53 may also be able to activate apoptosis independent of transcriptional regulation. Therefore, to ensure normal cell growth, p53 levels and activity are tightly regulated. Upon diverse forms of cellular stress the steady state levels and transcriptional activity of p53 are considerably increased. The stabilization and activation of p53 are a result of hindered inhibition by its negative regulators, e.g. Mdmx (also known as Mdm4) and Mdm2, while on the other hand activators such as HIPK2 and DYRK2 enhance the p53 response. The continually increasing understanding of the mechanisms of regulation of p53 may provide the basis for new drug designs that could eventually lead to therapeutics to reactivate p53 in cancers.
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PMID:p53: a guide to apoptosis. 1833 91


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