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)

Interferon (IFN)-gamma is a survival factor for mature erythroid progenitor cells. To elucidate related survival mechanisms, we compared the role of phosphatidylinositol 3-kinase (PI3-kinase) in the survival signals of IFN-gamma and erythropoietin (EPO). Human erythroid colony-forming cells (ECFCs) purified from peripheral blood were used, and Ly294002 was used as a PI3-kinase inhibitor. Treating ECFCs with a high concentration of Ly294002 (50 micromol/L) in the presence of EPO and/or IFN-gamma reduced cell viability by inducing apoptosis. However, treating cells with a lower concentration of Ly294002 (10 micromol/L) did not affect the antiapoptotic function of IFN-gamma and abolished the antiapoptotic effect of EPO. Adding IFN-gamma or EPO induced Bcl-x expression in ECFCs, as determined by Western blotting, and expression was suppressed in the presence of Ly294002. We also examined the phosphorylation of the protein kinase Akt, the downstream target of PI3-kinase. EPO stimulation significantly increased the level of Akt phosphorylation, but IFN-gamma did not. These results suggest that IFN-gamma plays a role in preventing the apoptosis of erythroid progenitor cells by affecting Bcl-x expression, thereby reducing the disruption of the mitochondrial transmembrane potential via PI3-kinase pathways that are related to but distinct from the EPO pathway.
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PMID:The signaling pathways of erythropoietin and interferon-gamma differ in preventing the apoptosis of mature erythroid progenitor cells. 1470 34

Accumulating data support the idea that apoptosis in cardiac myocytes, in part, contributes to the development of heart failure. Since a number of neurohormonal factors are activated in this state, these factors may be involved in the positive and negative regulation of apoptosis in cardiac myocytes. Norepinephrine is one such factor and induces apoptosis in cardiac myocytes via a beta-adrenergic receptor pathway. beta-adrenergic agonist-induced apoptosis in cardiac myocytes is dependent on the activation of the cAMP/protein kinase A pathway. Interestingly, the activation of this pathway protects PC12 cells from apoptosis, suggesting that cAMP/protein kinase A regulates apoptosis in a cell type-specific manner. Another neurohormonal factor activated in heart failure is endothelin-1, which acts as a potent survival factor against myocardial cell apoptosis. Intracellular signaling pathways for endothelin-1-mediated protection include activation of MEK-1 /ERK1/2 and PI3 kinase. In addition to these protective pathways common among cell types, endothelin- activates the calcium-activated phosphatase calcineurin, which is necessary for the nuclear import of NFAT transcription factors. These factors interact with the cardiac-restricted zinc finger protein GATA-4 and induce transcription and expression of anti-apoptotic molecule bcl-2. Thus, myocardial cell apoptosis is regulated by pathways unique to cardiac myocytes as well as by those common among cell types. It should be further determined whether agents that specifically block myocardial cell apoptosis will attenuate the progression of heart failure.
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PMID:Intracellular signaling pathways for norepinephrine- and endothelin-1-mediated regulation of myocardial cell apoptosis. 1512 20

Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A(1), A(2a), A(2b), A(3)) on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain-containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A(2) receptor agonists and was blocked by selective A(2a) and A(2b) receptor antagonists, indicating that adenosine was mediating its effect through A(2) receptors. Inhibition of STAT5a/b phosphorylation was reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A(2) receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells.
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PMID:Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. 1524 Jun 80

Approximately 65% of B cells generated in human bone marrow are potentially harmful autoreactive B cells. Most of these cells are clonally deleted in the bone marrow, while those autoreactive B cells that escape to the periphery are anergized or perish before becoming mature B cells. Escape of self-reactive B cells from tolerance permits production of pathogenic auto-antibodies; recent studies suggest that extended B lymphocyte survival is a cause of autoimmune disease in mice and humans. Here we report a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase Cdelta (PKCdelta): spontaneous death of resting B cells is regulated by nuclear localization of PKCdelta that contributes to phosphorylation of histone H2B at serine 14 (S14-H2B). We show that treatment of B cells with the potent B-cell survival factor BAFF ('B-cell-activating factor belonging to the TNF family') prevents nuclear accumulation of PKCdelta. Our data suggest the existence of a previously unknown BAFF-induced and PKCdelta-mediated nuclear signalling pathway which regulates B-cell survival.
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PMID:Regulation of B-cell survival by BAFF-dependent PKCdelta-mediated nuclear signalling. 1536 83

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1beta-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2alpha or kinase-inactive CK2alpha (K68M) or CK2alpha' (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2alpha expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression.
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PMID:Influence of casein kinase II in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human rhabdomyosarcoma cells. 1603 52

Many neurodegenerative diseases involve oxidative stress and excitotoxic cell death. In an attempt to further elucidate the signal transduction pathways involved in the cell death/cell survival associated with excitotoxicity, we have used an in vivo model of excitotoxicity employing kainic acid (KA)-induced neurotoxicity. Here, we show that extracellular signal-related kinase (ERK) 2, but not ERK 1, is phosphorylated and thereby activated in the hippocampus and cerebellum of kainic acid-treated mice. Phosphorylation and hence inactivation of glycogen synthase kinase 3beta (GSK-3beta), a general survival factor, is often a downstream consequence of mitogen-activated protein kinase pathway activation. Indeed, GSK-3beta phosphorylation occurred in response to kainic acid exclusively in the affected hippocampus, but not as a consequence of ERK activation. This may represent a compensatory attempt at self-protection by the cells in this particular brain region. A role for GSK-3beta inhibition in cell survival was further supported by the fact that pharmacological inhibition of GSK-3beta using lithium chloride was protective against kainic acid-induced excitotoxicity in hippocampal slice cultures. This work supports a role for GSK-3beta in cell death in response to excitotoxins in vivo and further confirms that GSK-3beta plays a role in cell death/cell survival pathways.
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PMID:Inactivation of glycogen synthase kinase-3beta protects against kainic acid-induced neurotoxicity in vivo. 1547 3

Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli, as well as being elevated in many human cancers examined. We have demonstrated that CK2 is a key survival factor that protects human colon carcinoma cells from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. We determined that inhibition of CK2 phosphorylation events by DRB (5,6-dichlorobenzimidazole) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis, in the absence of effects in normal cells. Sensitization was caspase dependent, and independent of regulation via NF-kappaB. Further, inhibition of phosphorylation by CK2 did not modify the expression level of antiapoptotic proteins. Analysis of TRAIL-induced death-inducing signaling complex (DISC) formation demonstrated enhanced formation of the DISC, enhanced cleavage of caspase-8 and cleavage of Bid in the presence of DRB, thereby facilitating the release of proapoptotic factors from the mitochondria with subsequent downregulation of the expression of XIAP and c-IAP1. Further, silencing of CK2alpha in HT29 cells following transfection of CK2alpha shRNA abrogated CK2 kinase activity while simultaneously increasing TRAIL sensitivity. These findings demonstrate that CK2 plays a critical antiapoptotic role by conferring resistance to TRAIL at the level of the DISC.
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PMID:Casein kinase II (CK2) enhances death-inducing signaling complex (DISC) activity in TRAIL-induced apoptosis in human colon carcinoma cell lines. 1568 23

Extracellular signal-regulated kinase (ERK) activation has been shown to promote neuronal death in various paradigms. We demonstrated previously that the late and sustained ERK activation in cerebellar granule neurons (CGNs) cultured in low potassium predominantly promotes plasma membrane (PM) damage. Here, we examined the effects of a well established neuronal survival factor, insulin-like growth factor 1 (IGF-1), on the ERK cell death pathway. Stimulation of CGNs with IGF-1 induced an early and transient ERK activation but abrogated the appearance of late and sustained ERK. Withdrawal or readdition of IGF-1 after 4 h in low potassium failed to prevent sustained ERK activation and cell death. IGF-1 activated the protein kinase A (PKA) to mediate ERK inhibition via c-Raf phosphorylation at an inhibitory site (Ser259). Phosphatidylinositol 3-kinase (PI3K) or PKA inhibitors, but not a specific Akt inhibitor, abrogated PKA signaling. This suggests that the PI3K/PKA/c-Raf-Ser259 pathway mediates ERK inhibition by IGF-1 independent of Akt. In addition, adenoviral-mediated expression of constitutively active MEK (mitogen-activated protein kinase kinase) or Sindbis viral-mediated expression of mutant Raf Ser259Ala both attenuated IGF-1-mediated prevention of PM damage. Activation of caspase-3 promoted DNA damage. Its inhibition by IGF-1 was both PI3K and Akt dependent but PKA independent. 8-Br-cAMP, an activator of PKA, induced phosphorylation of c-Raf-Ser259 and inhibited ERK activation without affecting caspase-3. This indicates a selective role for PKA in ERK inhibition through c-Raf-Ser259 phosphorylation. Together, these data demonstrate that IGF-1 can positively and negatively regulate the ERK pathway in the same neuronal cell, and provide new insights into the PI3K/Akt/PKA signaling pathways in IGF-1-mediated neuronal survival.
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PMID:Insulin-like growth factor 1 inhibits extracellular signal-regulated kinase to promote neuronal survival via the phosphatidylinositol 3-kinase/protein kinase A/c-Raf pathway. 1577 44

Ciliary neurotrophic factor (CNTF) exhibits multiple biological effects during vertebrate retinal development, including regulating the differentiation of photoreceptor cells and promoting the survival and axonal growth of ganglion cells. We report here that in addition to affecting the differentiation of retinal neurons, CNTF also promotes Muller glia genesis in the postnatal mouse retina. In both retinal monolayer and explant cultures, CNTF increases the number of progenitor cells adopting the Muller cell fate. Exogenous CNTF induces phosphorylation of signal transducers and activators of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) among neonatal progenitor cells and newborn Muller cells. In addition, increased levels of endogenous STAT3 and ERK phosphorylation have been observed at around postnatal day 5, coinciding with the peak of Muller glia genesis. Perturbation of STAT and ERK signaling using protein kinase inhibitors and a dominant-negative STAT3 mutant demonstrates that both CNTF-induced STAT and ERK activation are involved in promoting Muller cell production. Moreover, absorbing epidermal growth factor (EGF) signals with a neutralizing antibody did not affect CNTF-induced Muller glial genesis, indicating that the effect of CNTF is not mediated by the known Muller-enhancing activity of EGF. Together, these results support a novel function of CNTF-like cytokines in retinal gliogenesis.
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PMID:Ciliary neurotrophic factor promotes muller glia differentiation from the postnatal retinal progenitor pool. 1585 65

3,5,3'-triiodothyronine (T3) is essential for the growth and the regulation of metabolic functions, moreover, the growth-stimulatory effect of T3 has largely been demonstrated and the pathways via which T3 promotes cell growth have been recently investigated. Type 1 diabetes (T1D) is due to the destruction of beta-cells, which occurs even through apoptosis. Aim of our study was to analyze whether T3 could have an antiapoptotic effect on cultured beta-cells undergoing apoptosis. We have demonstrated that T3 promotes cell proliferation in islet beta-cell lines (rRINm5F and hCM) provoking an increment in cell number (up to 55%: rRINm5F and 45%: hCM), cell viability, and BrdU incorporation, and regulating the cell cycle-related molecules (cyc A, D1, E, and p27(kip1)). T3 inhibited the apoptotic process induced by streptozocin, S-Nitroso-N-Acetylpenicylamine (SNAP), and H2O2 via regulation of the pro- and anti-apoptotic factors Bcl-2, Bcl-XL, Bad, Bax, and Caspase 3. The T3 protective effect was PI-3 K-, but not MAPK- or PKA-mediated, involving pAktThr308. Thus, T3 could be considered a survival factor protecting islet beta-cells from apoptosis.
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PMID:3,5,3'-triiodothyronine (T3) is a survival factor for pancreatic beta-cells undergoing apoptosis. 1602 36


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