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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dystroglycan is a component of the dystrophin-glycoprotein complex (DGC) in muscle and a cell surface receptor for laminin. Numerous muscular dystrophies are the result of disruption of proteins comprising the DGC, but the underlying pathogenetic mechanisms are unknown. Because apoptosis is an early feature of muscular dystrophy in vivo, and perturbation of cell-extracellular matrix associations is known to induce apoptosis, we investigated the role of dystroglycan-laminin interactions in the propagation and maintenance of cell survival signals in muscle cells. We found that disrupting the interaction between alpha-dystroglycan and the extracellular matrix protein laminin induces apoptosis in muscle cells. This increase in apoptosis is mediated in part by caspase activation and can be blocked by a caspase-3 inhibitor. We demonstrate a role for the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in muscle cell-survival signaling using a pharmacological inhibitor of PI3K. Treatment with this inhibitor resulted in decreased phosphorylation of AKT and its downstream effector glycogen synthase kinase (GSK)-3beta and induced apoptosis in muscle cell cultures. Disruption of dystroglycan-laminin interactions resulted in decreased phosphorylation of AKT and GSK-3beta. Furthermore, activation of AKT prior to the disruption of dystroglycan-laminin protected the muscle cells from the induction of apoptosis. These results support a role for the PI3K/AKT pathway in the propagation of cell-survival signals mediated by the DGC and provide new insight into the molecular pathogenesis associated with the development of muscular dystrophies.
...
PMID:Inhibition of dystroglycan binding to laminin disrupts the PI3K/AKT pathway and survival signaling in muscle cells. 1240 86

The mechanisms by which cells adapt and respond to changes in oxygen tension remain largely unknown. Our laboratory has used the PC12 cell line to study both biophysical and molecular responses to hypoxia. This chapter summarizes our findings. We found that membrane depolarization that occurred when PC12 cells were exposed to reduced O(2) was mediated by a specific potassium channel, the Kv1.2 channel. The membrane depolarization leads to increased Ca(2+) conductance through a voltage-sensitive channel, which in turn mediates the release of the neurotransmitters dopamine, adenosine, glutamate, and GABA. In addition, increased intracellular Ca(2+) and other signaling systems regulate hypoxia-induced gene expression, which contributes to the adaptive response to reduced O(2+). We identified several critical signaling pathways that regulate a complex gene expression profile in PC12 cells during hypoxia. These include the cAMP-protein kinase A, Ca(2+)-calmodulin, p42/44 mitogen-activated protein kinase (MAPK), stress-activated protein kinase (SAPK; p38 kinase), and the phosphatidylinositol 3-kinase-AKT as regulators of gene expression. Several of these pathways regulate hypoxia-specific transcription factors that are members of the hypoxia-inducible factor (HIF) family. Recently, we have successfully used subtractive cDNA libraries and microarray analysis to identify the genomic profile that mediates the cellular response to hypoxia.
...
PMID:Genomic and physiological analysis of oxygen sensitivity and hypoxia tolerance in PC12 cells. 1243 56

Selenium has been implicated as a promising chemopreventive agent for prostate cancer. Whereas the anticancer mechanisms have not been clearly defined, one hypothesis relates to selenium metabolites, especially the monomethyl selenium pool, generated under supranutritional selenium supplementation. To explore potential molecular targets for mediating the chemopreventive activity, we contrasted the effects of methylseleninic acid (MSeA), a novel precursor of methylselenol, versus sodium selenite, a representative of the hydrogen selenide metabolite pool, on apoptosis execution, cell cycle distribution, and selected protein kinases in DU145 human prostate cancer cells. Exposure of DU145 cells to 3 microM MSeA led to a profound G1 arrest at 24 h, and exposure to greater concentrations led to not only G1 arrest, but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical hallmarks of apoptosis. Immunobiot analyses indicated that G1 arrest induced by the subapoptogenic doses of MSeA was associated with increased expression of p27kip1 and p21cip1, but apoptosis was accompanied by dose-dependent decreases of phosphorylation of protein kinase AKT and extracellular signal-regulated kinase (ERK1/2) in the absence of any phosphorylation change in p38 mitogen-activated protein kinase (p38MAPK) and c-Jun NH2-terminal kinase (JNK1/2). In contrast, selenite exposure caused S-phase arrest and caspase-independent apoptotic DNA fragmentation, which were associated with decreased expression of p27kip1 and p21cip1 and increased phosphorylation of AKT, JNK1/2, and p38MAPK. Although apoptosis induction by MSeA exposure was not sensitive to superoxide dismutase added into the cell culture medium, cell detachment and DNA nucleosomal fragmentation induced by selenite exposure were greatly attenuated by this enzyme, supporting a chemical mediator role of superoxide for these processes. Despite a temporal relationship of AKT and ERK1/2 de-phosphorylation changes before the onset of PARP cleavage in MSeA-exposed cells, experiments with phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 did not show an enhancing effect of specific blocking of AKT on MSeA-induction of PARP cleavage. Taken together, exposure of DU145 cells to MSeA versus selenite induced differential patterns of cell cycle arrest and apoptosis execution as well as distinct patterns of effects on AKT, ERK1/2, JNK1/2, and p38MAPK phosphorylation and p27kip1 and p21cip1 expression. Multiple molecular pathways are likely differentially targeted by selenium metabolite pools to mediate cancer chemoprevention.
...
PMID:Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells. 1248 29

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin receptor (IR) signal transduction and a drug target for treatment of type 2 diabetes. Using PTP1B antisense oligonucleotides (ASOs), effects of decreased PTP1B levels on insulin signaling in diabetic ob/ob mice were examined. Insulin stimulation, prior to sacrifice, resulted in no significant activation of insulin signaling pathways in livers from ob/ob mice. However, in PTP1B ASO-treated mice, in which PTP1B protein was decreased by 60% in liver, similar stimulation with insulin resulted in increased tyrosine phosphorylation of the IR and IR substrate (IRS)-1 and -2 by threefold, fourfold, and threefold, respectively. IRS-2-associated phosphatidylinositol 3-kinase activity was also increased threefold. Protein kinase B (PKB) serine phosphorylation was increased sevenfold in liver of PTP1B ASO-treated mice upon insulin stimulation, while phosphorylation of PKB substrates, glycogen synthase kinase (GSK)-3alpha and -3beta, was increased more than twofold. Peripheral insulin signaling was increased by PTP1B ASO, as evidenced by increased phosphorylation of PKB in muscle of insulin-stimulated PTP1B ASO-treated animals despite the lack of measurable effects on muscle PTP1B protein. These results indicate that reduction of PTP1B is sufficient to increase insulin-dependent metabolic signaling and improve insulin sensitivity in a diabetic animal model.
...
PMID:Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. 1250 89

Protein kinase B (PKB) is the expression product of a proto-oncongen (c-akt), which is involved in the signaling pathways initiated by some growth factors and mediated by phosphoinositide 3-kinase (PI3K). PKB is a direct target of PI3K. Similar to many protein kinases, PKB has a specific AH/PH domain which can mediate the interaction between signaling molecules. The lipid second messengers, PI-3, 4-P2 and PI-3,4,5-P3 produced by PI3K, can bind to the AH/PH domain of PKB and of PDK (phosphoinositide dependent protein kinase). This binding translocates PKB and PDK to the plasma membrane, and activates them. PKB is also activated via phosphorylation by PDK and, in turn, will activate the anti-apoptotic machinery, glucose metabolism (glycogen synthesis, glycolysis and glucose uptake) and protein synthesis. All these lead to cell growth and proliferation.
...
PMID:[Protein kinase B and its role in the signal transduction pathway mediated by phosphoinositide 3-kinase]. 1254 28

Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.
...
PMID:Role of protein kinase B in Alzheimer's neurofibrillary pathology. 1262 92

The role of integrin-linked kinase (ILK), a kinase that is involved in various cellular processes, including adhesion and migration, has not been studied in primary neurons. Using mRNA dot blot and Western blot analysis of ILK in rat and human brain tissue, we found that ILK is expressed in various regions of the CNS. Immunohistochemical and immunocytochemical techniques revealed granular ILK staining that is enriched in neurons and colocalizes with the beta1 integrin subunit. The role of ILK in neurite growth promotion by NGF was studied in rat pheochromocytoma cells and dorsal root ganglion neurons using a pharmacological inhibitor of ILK (KP-392) or after overexpression of dominant-negative ILK (ILK-DN). Both molecular and pharmacological inhibition of ILK activity significantly reduced NGF-induced neurite outgrowth. Survival assays indicate that KP-392-induced suppression of neurite outgrowth occurred in the absence of cell death. ILK kinase activity was stimulated by NGF. NGF-mediated stimulation of phosphorylation of both AKT and the Tau kinase glycogen synthase kinase-3 (GSK-3) was inhibited in the presence of KP-392 and after overexpression of ILK-DN. Consequently, ILK inhibition resulted in an increase in the hyperphosphorylation of Tau, a substrate of GSK-3. Together these findings indicate that ILK is an important effector in NGF-mediated neurite outgrowth.
...
PMID:Role of integrin-linked kinase in nerve growth factor-stimulated neurite outgrowth. 1262 68

The Kinetworks trade mark multi-immunoblotting technique was used to evaluate the expressions of 78 protein kinases, 24 protein phosphatases and phosphorylation states of 31 phosphoproteins in thoracic spinal cord tissue from control subjects and patients having the sporadic form of amyotrophic lateral sclerosis (ALS). In both the cytosolic (C) and particulate (P) fractions of spinal cord from ALS patients as compared with controls, there were increased levels of calcium/calmodulin-dependent protein kinase kinase (CaMKK; C = 120% increase/P = 580% increase;% change, compared with control), extracellular regulated kinase 2 (ERK2; C = 120% increase/P = 170% increase), G protein-coupled receptor kinase 2 (GRK2; C = 140% increase/P = 140% increase), phospho-Y279/216 glycogen synthase kinase 3 alpha/beta (GSK3alpha/beta; C = 90% increase/P = 220% increase), protein kinase B alpha (PKBalpha; C = 360% increase/P = 200% increase), phospho-T638 PKCalpha/beta (C = 630% increase/P = 170% increase), cGMP-dependent protein kinase (PKG; C = 100% increase/P = 75% increase), phospho-T451 dsRNA-dependent protein kinase (PKR; C = 2600% increase/P = 3330% increase), ribosomal S6 kinase 1 (RSK1; C = 750% increase/P = 630% increase), phospho-T389 p70 S6 kinase (S6K; C = 1000% increase/P = 460% increase), and protein-tyrosine phosphatase 1 delta (PTP1delta; C = 43% increase/P = 70% increase). Cytosolic increases in phospho-alpha-S724/gamma-S662 adducin (C = 15650% increase), PKCalpha (C = 100% increase) and PKCzeta (C = 190% increase) were found in ALS patients as compared with controls, while particulate increases in cAMP-dependent protein kinase (PKA; 43% increase), protein kinase C beta (PKCbeta; 330% increase), and stress-activated protein kinase beta (SAPKbeta; 34% increase) were also observed. Cyclin-dependent kinase-associated phosphatase (KAP) was apparently translocated, as it was reduced (31% decrease) in cytosolic fractions but elevated (100% increase) in particulate fractions of ALS spinal cord tissue. Our observations indicate that ALS is associated with the elevated expression and/or activation of many protein kinases, including PKCalpha, PKCbeta, PKCzeta and GSK3alpha/beta, which may augment neural death in ALS, and CaMKK, PKBalpha, Rsk1, S6K, and SAPK, which may be a response to neuronal injury that potentially can mitigate cell death.
...
PMID:Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. 1267 19

CKI p21 is a regulator of cellular responses to microtubule damage induced by drugs such as paclitaxel (PTX). It mediates the G1 4N arrest postactivation of the spindle assembly checkpoint and protects cancer cells against PTX-induced cytotoxicity. We demonstrated here that low doses of PTX that are unable to activate the spindle assembly checkpoint, upregulate p21 by a p53-dependent pathway and induce its translocation to the cytoplasm. This cytoplasmic accumulation of p21 resulted from an AKT-dependent p21 phosphorylation leading to an association of p21 with 14-3-3. Furthermore, the cytoplasmic p21 accumulation observed in PTX-treated cells was inhibited by LY 294002, a specific PI-3 kinase inhibitor or by the expression of a dominant-negative AKT mutant. However, the kinase activity of AKT was unchanged in PTX-treated cells, suggesting that low doses of PTX could regulate p21 phosphorylation via inhibition of its dephosphorylation. As a functional consequence, we found that cytoplasmic accumulation of the phosphorylated form of p21 prevents the inhibitory effect of p21, enabling these cells to escape to the p53-dependent Gl/S and G2/M checkpoints.
...
PMID:Paclitaxel increases p21 synthesis and accumulation of its AKT-phosphorylated form in the cytoplasm of cancer cells. 1276 96

The serine/threonine kinase AKT, also known as PKB or RAC-PK, is a key molecule for protecting cells from undergoing apoptosis. Several studies have suggested that the AKT-mediated survival-signaling pathway is an attractive target for cancer chemotherapy: (1) the AKT pathway is relatively inactive in resting cells; (2) amplification of the AKT gene occurs in some tumors; (3) loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) is common in tumors and its loss constitutively activates AKT; (4) AKT is activated at the cancer invasion front. To clarify which drugs exhibit their cytotoxicity by inhibiting the AKT pathway, we screened anticancer drugs that could downregulate phospho-AKT levels and AKT kinase activity. We found that UCN-01 (7-hydroxystaurosporine), heat-shock protein 90 (HSP90) inhibitors, and topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin) possessed the ability to interfere with the AKT pathway. UCN-01 directly suppressed upstream AKT kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) (IC(50) <33 nM) both in vitro and in tumor xenografts. HSP90 inhibitors and topotecan suppressed AKT activity via indirectly downregulating PDK1 and phosphatidylinositide-3-OH kinase activities. Transfection of the constitutively active AKT complementary DNA into cells attenuated the cytotoxic effects of the drugs, indicating that inhibition of the AKT pathway plays an important role in exerting their cytotoxic effects. These results strongly suggest that the AKT-mediated survival-signaling pathway is a promising and attractive target for cancer chemotherapy.
...
PMID:Survival-signaling pathway as a promising target for cancer chemotherapy. 1281 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---