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)

We identified Ran-binding protein (RanBPM) as an interacting partner of the caspase-processed C-terminal domain of cyclin-dependent kinase 11 (CDK11(p46)) by using the yeast two-hybrid system. CDK11(p110) protein kinases are members of the cyclin-dependent kinase superfamily. During staurosporine-, Fas-, and tumor necrosis factor alpha-induced apoptosis caspase-processed activated CDK11(p46) is generated from larger CDK11(p110) isoforms. CDK11(p46) promotes apoptosis when it is ectopically expressed in human cells. However, the mechanism of signal transduction through CDK11(p46) is still unclear. In this study, we demonstrate that CDK11(p46) directly interacts with RanBPM in vitro and in human cells. RanBPM contains a conserved SPRY (repeats in splA and Ryr) domain and is localized both in the nucleus and cytoplasm. The SPRY domain of RanBPM is responsible for the association between CDK11(p46) and RanBPM. Furthermore, we show that CDK11(46) phosphorylates RanBPM.
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PMID:The cyclin-dependent kinase 11(p46) isoform interacts with RanBPM. 1451 41

Elevated expression of IL-10 has been frequently observed in tumor tissues and tumor-infiltrating cells. We show herein that transcription of the IL-10 gene in primary peripheral T cells and T cell lines is up-regulated upon contact with glioma cells without an induction of apoptosis in those T cells. Glioma-associated IL-10 induction was suppressed by interrupting the engagement of Fas and its ligand (Fas-L) with the antagonistic Ab, ZB4, by reducing Fas-L expression of glioma cells using the Fas-L-specific ribozyme, or by preventing cell-to-cell contact in a Transwell culture setting. Cross-linking of Fas with the agonistic Ab, CH-11, triggered apoptosis and enhanced the expression of IL-10 in Jurkat cells at the transcriptional and translational levels. Inhibiting caspase activities by caspase inhibitors, Z-VAD (Z-Val-Ala-Asp(Ome)-fluoromethylketone) and Z-IETD (Z-Ile-Glu(Ome)-Thr(Ome)-Asp(Ome)-fluoromethylketone), abolished this IL-10 induction in Jurkat cells. Intracellular staining detected IL-10 proteins in Fas-cross-linked Jurkat cells and in PHA-activated T cells. However, few IL-10 proteins were detectable in Jurkat cells cocultured with glioma cells, indicating a requirement of other factors for IL-10 production. Direct activation of protein kinase A (PKA) by forskolin elevated the transcription of IL-10 in Jurkat cells. However, KT5720, a selective PKA inhibitor, reduced neither anti-Fas-triggered nor glioma-associated IL-10 expression. Phosphorylation of cAMP response element binding protein and activating transcription factor-1 in Jurkat cells was not affected by coculturing with glioma cells or by anti-Fas treatment, further suggesting a PKA-independent pathway. In summary, our results demonstrate nonlethal cross-talk between tumor and immune cells leading to IL-10 dysregulation in T cells, which might contribute to Fas-L(+) tumor-associated immunosuppression.
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PMID:Mediation of enhanced transcription of the IL-10 gene in T cells, upon contact with human glioma cells, by Fas signaling through a protein kinase A-independent pathway. 1453 Mar 12

Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein (RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2-/- mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-xL, p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection.
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PMID:A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. 1453 86

Individuals affected with tuberous sclerosis complex (TSC) develop cortical tubers characterized by disorganized cytoarchitecture and morphologically abnormal cell types, such as dysplastic neurons (DNs) and giant cells (GCs). As part of ongoing cDNA array analysis to study the molecular pathogenesis of tuber formation, we detected increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, a cell adhesion molecule (CAM) that functions in cytokine signaling, in tubers. Western and immunohistochemical analyses revealed that ICAM-1 protein was selectively expressed in tubers, but was only minimally expressed in control cortex, adjacent nontuberal cortex, or in non-TSC focal cortical dysplasia. Increased expression of ICAM-1 was found in mice in which the Tsc1 gene was conditionally inactivated in astrocytes. Expression of molecules involved in ICAM-1 activation and cytokine signaling were increased in tubers, including tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB). Numerous CD68-immunoreactive macrophages were observed clustered around GCs further supporting an inflammatory response in tubers. Expression of caspase 8 and Fas support cytokine activation and detection of TUNEL reactivity suggests ongoing cell death in tubers. Specific alterations in ICAM-1, TNF-alpha, NF-kappaB1, and MAPK expression coupled with the detection of numerous CD68-immunoreactive macrophages suggests activation of proinflammatory cytokine signaling pathways in tubers that may culminate in cell death.
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PMID:Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex. 1457 49

Calmodulin (CaM) antagonists have been shown to inhibit tumor cell invasion and metastasis and to induce apoptosis in various tumor models, but the molecular mechanism of CaM antagonist-mediated apoptosis is poorly understood. Here, we demonstrate that interferon (IFN)-gamma induces susceptibility to CaM antagonist-mediated apoptosis in human cholangiocarcinoma cells weakly expressing Fas (Fas-low cells). During CaM antagonist-mediated apoptosis in IFN-gamma-pretreated Fas-low cells, cleavage of caspases-8, -9, and -3 and Bid, release of cytochrome c from the mitochondria and an increase in the free cytosolic calcium concentration were observed. CaM antagonists also caused depolarization of the mitochondrial membrane independent of caspase activation. Although a broad-range caspase inhibitor partially blocked CaM antagonist-mediated apoptosis, the neutralizing Fas antibody had no effect, suggesting that CaM antagonist-mediated apoptosis does not require interaction between CaM antagonists and surface Fas. CaM antagonists induce apoptosis via mechanisms other than inhibition of CaM-dependent protein kinase II and calcineurin, as their inhibitors, KN93 and cyclosporine A, had no effect on apoptosis. Taken together, these results indicate that CaM antagonists induce apoptosis in both caspase-dependent and -independent manners, and that susceptibility to CaM antagonists is modulated by IFN-gamma. The combination of IFN-gamma and CaM antagonists, including tamoxifen, may be a potential therapeutic modality for cholangiocarcinoma and possibly other malignancies.
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PMID:The combination of calmodulin antagonists and interferon-gamma induces apoptosis through caspase-dependent and -independent pathways in cholangiocarcinoma cells. 1457 4

Viruses have evolved different strategies to interfere with apoptotic pathways in order to halt cellular responses to infection. The herpes simplex virus 1 (HSV-1) Us3 open-reading frame encodes a serine/threonine protein kinase that participates in the inhibition of apoptosis induced by virus infection and other stress agents. Previous studies have shown that Us3 counteracts the virus-induced activation of caspase-3 by acting at a premitochondrial stage. Using stable transfectants that express Us3 under the control of constitutive or inducible promoters we demonstrate that apoptosis induced by treatment with anti-Fas antibody and sorbitol is blocked when Us3 is expressed at levels comparable to those achieved during virus infection. Expression of Us3 correlated with phosphorylation of Bad, a BH3-only proapoptotic Bcl-2 family member that is also a target for growth factor-induced cellular kinases. Bad was phosphorylated by Us3 in in vitro kination assays. These results point to a strategy for viral inhibition of apoptosis based on functional inactivation of a critical component of the cellular death machinery.
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PMID:The Us3 protein kinase of herpes simplex virus 1 blocks apoptosis and induces phosporylation of the Bcl-2 family member Bad. 1459 23

Many viruses including influenza virus induce apoptosis of host cells. Influenza virus-induced apoptosis shares common features of apoptosis, i.e. activation of caspases and inhibition by bcl-2. Fas and its ligand and double stranded-RNA activated-protein kinase (PKR) are partly involved in the apoptosis. Virus proteins as nonstructural protein I, neuraminidase as well as a novel protein, PB1-F2, play some roles in promoting the virus-induced apoptosis. Apoptotic cells are effectively engulfed by macrophages, which recognize phosphatidylserine on the outer leaflet of the membrane of apoptotic cell. Neuraminidase activity is required for the effective phagocytosis. All these evidence suggest that the virus-induced apoptosis is one of the mechanisms of host defense system.
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PMID:[Influenza virus infection and apoptosis]. 1461 45

Previous studies have demonstrated that cotreatment with mitogen activated-protein kinase kinase (MEK) 1/2 inhibitors (e.g., PD184352) and the checkpoint abrogator 7-hydroxystaurosporine (UCN-01) dramatically induces apoptosis in a variety of human leukemia and multiple myeloma cell types. The purpose of this study was to evaluate the roles of Bcl-2 family members and the relative contribution of the intrinsic mitochondrial versus the extrinsic receptor-related apoptotic pathways to MEK inhibitors/UCN-01-induced leukemic cell death. Cotreatment of U937 cells with PD184352 and UCN-01 resulted in the activation of procaspase-3, -9, and -8 as well as Bid cleavage. PD184352/UCN-01-induced mitochondrial dysfunction and apoptosis were both substantially attenuated in cells ectopically expressing Bcl-2, an N-terminal phosphorylation loop-deleted mutant Bcl-2, or Bcl-xL, but not in cells expressing dominant-negative (DN) caspase-8, cytokine response modifier A (cowpox virus-encoded antiapoptotic protein), or DN Fas-associated death domain. Coadministration of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or TNF-alpha substantially increased MEK inhibitors (e.g., PD184352 or U0126)/UCN-01-induced mitochondrial dysfunction, activation of procaspase-8 and Bid, and apoptosis in Bcl-2- and Bcl-xL-overexpressing cells but not in those in which the extrinsic pathway was interrupted. Together, these findings suggest that the MEK inhibitors/UCN-01 regimen primarily induces leukemic cell apoptosis by engaging the intrinsic, mitochondrial apoptotic pathway and that resistance to these events conferred by increased expression of certain antiapoptotic Bcl-2 family members can be overcome, at least in part, by coadministration of TRAIL and other agents that activate the extrinsic apoptotic cascade.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes mitochondrial dysfunction and apoptosis induced by 7-hydroxystaurosporine and mitogen-activated protein kinase kinase inhibitors in human leukemia cells that ectopically express Bcl-2 and Bcl-xL. 1464 70

The proliferative compartment of the intestinal crypt is critical in the process of intestinal epithelial cell homeostasis. The ability of these progenitor crypt cells to resist apoptosis and ensure restitution during a potentially lethal insult, but retain the ability to remove damaged or altered cells afterward, is necessary for preservation of the crypt-villus unit. We have examined the ability of cAMP to transiently inhibit apoptosis via the extracellular signal-regulated kinases 1 and 2 (ERK1/2), in T84 cells, an intestinal crypt-like cell line. Using the cAMP analog 8-bromo-cAMP and cholera toxin (CT), cAMP-mediated ERK1/2 activation was first measured by Western blot analysis of the phosphorylated (activated) and total (activated and inactivated) forms of ERK1/2. Cyclic AMP activated ERK1/2 in a time- and dose-dependent manner, and the effect was inhibited by PD098059, an inhibitor of the ERK1/2 signaling pathway. However, inhibition of protein kinase A (PKA) did not alter the activation of ERK1/2. CT transiently inhibited both staurosporine and Fas antibody mediated apoptosis as measured by a caspase-3 activation assay and the detection of nucleosomes in an apoptosis based enzyme-linked immunosorbent assay. This inhibitory effect was reversed by the simultaneous addition of PD098059. Our data suggest that in the T84 cell line, cAMP activates ERK1/2 in a PKA independent fashion and a physiological consequence of this activated pathway is the transient inhibition of apoptosis. These findings suggest a novel pathway that intestinal cells use to protect against injury while maintaining the overall ability to remove damaged cells and preserve intestinal homeostasis.
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PMID:Cyclic AMP activation of the extracellular signal-regulated kinases 1 and 2: implications for intestinal cell survival through the transient inhibition of apoptosis. 1474 67

We employed potent and selective c-Src inhibitors to investigate the functional and molecular consequences of inhibited c-Src tyrosine kinase activity in osteoclasts. These pyrrolopyrimidine derivatives reduced osteoclast numbers and induced osteoclast disruption in vivo. In vitro, they inhibited resorption pit formation and osteoclastogenesis, impaired adhesion ability and actin ring organization, and induced programmed cell death in mature osteoclasts. The cell death receptor Fas and p53 were insensitive to c-Src modulation. The expression of the cyclin-dependent kinase (CDK)-inhibitor p21WAF1/CIP1 was markedly reduced, but neither Bcl-2 nor Bcl-xL or Bax were modulated by c-Src inhibition. Caspase-9, and to a lesser extent caspase-3, but not caspase-8, were transiently cleaved (activated) by treatment with the c-Src inhibitors. c-Src inhibition stabilized p38 mitogen-activated protein kinase (MAPK), whereas the c-Jun N-terminal kinase (JNK) pathway did not appear to be modulated by our compounds. Most interestingly, transient extracellular signal regulated kinase (ERK1/2) dephosphorylation followed by sustained remarkable rephosphorylation overwhelming control levels was observed in response to c-Src inhibition. Blockade of ERK1/2 rephosphorylation by PD98059 reduced osteoclast nuclear disruption, suggesting the involvement of this pathway in apoptosis. Collectively, these data demonstrate that small pyrrolopyrimidine derivatives impair osteoclast function and induce cell damage suggestive of apoptosis in vivo and in vitro, with mechanisms presumably involving selective sustained ERK1/2 phosphorylation.
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PMID:Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway. 1475 64


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