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)

Fas is a well characterized apoptosis-inducing factor. One of our synthetic compounds, MT-21, induced apoptosis in human leukemia HL-60 cells similar to Fas. MT-21 activated caspase-3, an important cysteine aspartic protease for apoptosis induction. MT-21 also activated c-Jun-NH2-terminal kinase (JNK), a member of mitogen activated protein kinase (MAPK) superfamily that is involved in the regulation of cell growth, differentiation and cell death. Moreover, MT-21 treatment resulted in the activation of a 36 kDa kinase which uses myelin basic protein (MBP) as a substrate. However, MAPK and p38 were not activated by treatment with MT-21. The 36 kDa MBP kinase was shown to be a proteolytic product derived from the Krs protein with a molecular weight of 60 kDa. The Krs protein is a Ser/Thr protein kinase whose activity is enhanced by digestion of its C-terminal regulatory domain by caspase-3. When a kinase-inactive mutant form of Krs protein was overexpressed in HL-60 cells, JNK activation and apoptosis induction by MT-21 were suppressed. Furthermore, overexpression of dominant negative c-Jun also suppressed apoptosis induction by MT-21. These findings indicate that MT-21 induces apoptosis by the activation of JNK via the Krs protein, which is activated by caspase cleavage.
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PMID:Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis. 1049 71

Neutral sphingomyelinase (N-SMase) has emerged as an important cell membrane-associated enzyme that participates in several signal transduction and cell regulatory phenomena. Using expression cloning, we have identified a 3.7-kilobase pair cDNA transcript for N-SMase whose open reading frame predicts a 397-amino acid polypeptide. Transfection of COS-7 cells with cDNA for N-SMase resulted in a marked increase in N-SMase activity. Recombinant N-SMase (r-N-SMase) had the following physical-chemical properties. Mg(2+) activated and Cu(2+) and glutathione inhibited the activity of r-N-SMase. In contrast, dithiothreitol did not alter the activity of the enzyme. Of several phospholipids examined, sphingomyelin was the preferred substrate for r-N-SMase. The apparent molecular mass of r-N-SMase derived from COS-7 cells was approximately 90 kDa, similar to the native neutral sphingomyelinase prepared from human urine. However, upon expression in Escherichia coli, the apparent molecular mass of the recombinant enzyme was approximately 45 kDa. We speculate that this apparent difference in recombinant enzymes derived from COS-7 and E. coli cells may be due to extensive post-transcriptional changes. r-N-SMase has numerous post-transcriptional modification sites such as phosphorylation sites via protein kinase C, casein kinase II, tyrosine kinase, and cAMP- and cGMP-dependent protein kinases as well as sites for glycosylation and myristoylation. Amino acid sequence alignment studies revealed that r-N-SMase has some similarity to acid sphingomyelinase and significant homology to the death domains of tumor necrosis factor-alpha receptor-1 and Fas/Apo-I. We believe that the molecular cloning and characterization of N-SMase cDNA will accelerate the process to define its role as a key regulator in apoptosis, lipid and lipoprotein metabolism, and other cell regulatory pathways.
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PMID:Molecular cloning, characterization, and expression of a novel human neutral sphingomyelinase. 1060 12

To identify essential components of the Fas-induced apoptotic signaling pathway, Jurkat T lymphocytes were chemically mutagenized and selected for clones that were resistant to Fas-induced apoptosis. We obtained five cell lines that contain mutations in the adaptor FADD. All five cell lines did not express FADD by immunoblot analysis and were completely resistant to Fas-induced death. Complementation of the FADD mutant cell lines with wild-type FADD restored Fas-mediated apoptosis. Fas activation of caspase-2, caspase-3, caspase-7, and caspase-8 and the proteolytic cleavage of substrates such as BID, protein kinase Cdelta, and poly(ADP-ribose) polymerase were completely defective in the FADD mutant cell lines. In addition, Fas activation of the stress kinases p38 and c-Jun NH2 kinase and the generation of ceramide in response to Fas ligation were blocked in the FADD mutant cell lines. These data indicate that FADD is essential for multiple signaling events downstream of Fas.
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PMID:FADD is required for multiple signaling events downstream of the receptor Fas. 1061 4

This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to 19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >> enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism.
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PMID:Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. 1077 Feb 86

Previously we have reported that induction of apoptosis in Jurkat cells results in an inhibition of overall protein synthesis with the selective and rapid cleavage of eukaryotic initiation factor (eIF) 4GI. For the cleavage of eIF4GI, caspase-3 activity is both necessary and sufficient in vivo, in a process which does not require signaling through the p38 MAP kinase pathway. We now show that activation of the Fas/CD95 receptor promotes an early, transient increase in the level of eIF2alpha phosphorylation, which is temporally correlated with the onset of the inhibition of translation. This is associated with a modest increase in the autophosphorylation of the protein kinase activated by double-stranded RNA. Using a Jurkat cell line that is deficient in caspase-8 and resistant to anti-Fas-induced apoptosis, we show that whilst the cleavage of eIF4GI is caspase-8-dependent, the enhancement of eIF2alpha phosphorylation does not require caspase-8 activity and occurs prior to the cleavage of eIF4GI. In addition, activation of the Fas/CD95 receptor results in the caspase-8-dependent dephosphorylation and degradation of p70(S6K), the enhanced binding of 4E-BP1 to eIF4E, and, at later times, the cleavage of eIF2alpha. These data suggest that apoptosis impinges upon the activity of several polypeptides which are central to the regulation of protein synthesis and that multiple signaling pathways are involved in vivo.
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PMID:Differential requirements for caspase-8 activity in the mechanism of phosphorylation of eIF2alpha, cleavage of eIF4GI and signaling events associated with the inhibition of protein synthesis in apoptotic Jurkat T cells. 1090 26

Caspase 3 is an essential factor for Fas-mediated cell death and exists endogenously in cells where its activation is suppressed by p21 and ILP. Inside the cell, procaspase 3 interacts with p21 on mitochondria. In the present study, we investigated the molecular basis for procaspase 3/p21 complex formation. During Fas-mediated cell death, mitochondria are damaged, accompanied by decreased mitochondrial membrane-potential and decreased intracellular ATP levels. This mitochondrial damage occurs before an estrangement of the procaspase 3/p21 complex, and we demonstrate that intracellular ATP-deprivation also initiates an estrangement of procaspase 3/p21 complex formation and accelerates Fas-mediated cell death. In addition, our current results revealed that the phosphorylated p21 by PKA interacts with procaspase 3. Here, we report that the mitochondrial role, especially for ATP synthesis, and PKA are necessary for the procaspase 3/p21 complex formation to resist Fas-mediated cell death.
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PMID:Procaspase 3/p21 complex formation to resist fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A. 1091 46

The interferon-induced dsRNA-dependent protein kinase (PKR) induces apoptosis of mammalian cells. Apoptosis induction by PKR involves phosphorylation of the translational factor eIF-2alpha and activation of the transcriptional factor NF-kappaB, but caspase pathways activated by PKR are not known. Upregulation of Fas mRNA by PKR has been suggested to play a role in PKR-induced apoptosis. To learn how PKR induces apoptosis, we have analysed the role of molecules in death receptor pathways. We showed the involvement of the FADD-caspase 8 pathway on PKR-induced apoptosis based on four experimental findings: upregulation of caspase 8 activity during PKR-induced apoptosis, blocking of PKR-induced apoptosis by the use of a chemical inhibitor of caspase 8, and inhibition of PKR-induced apoptosis by expression of both a FADD dominant negative or a viral FLIP molecule. Significantly, despite the PKR-mediated upregulation of Fas mRNA expression, the Fas receptor-ligand pathway is not needed for PKR-induced apoptosis. Antibodies that inhibit TNFalpha-TNFR1 or Fas-FasL interactions were not able to block PKR-induced apoptosis. Taken together, our observations establish the involvement of caspase 8 in PKR-induced apoptosis and suggest that death receptors other than Fas or TNFR1 or, alternatively, a novel mechanism involving FADD independently of death receptors, are responsible for PKR-induced apoptosis.
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PMID:The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-alpha receptors. 1095 73

The immunological consequences of apoptosis have been hotly debated. Apoptosis was originally described as a set of cellular morphological changes that occur in the absence of inflammation but the term has been redefined on the basis of a set of conserved molecular events that include the activation of caspases. Though the apoptosis occurring during normal development is immunologically bland or even tolerizing, the apoptotic death after viral infection or after the ligation of Fas can trigger powerful innate and adaptive immune responses. The molecular machinery at the nexus of apoptosis and inflammation includes caspase-1 --an activator of IL-1beta and IL-18 - as well as the double-stranded-RNA-dependent protein kinase pathway and RNaseL pathway, which are key effectors of antiviral immunity. New proapoptotic vaccines induce immune responses that may be able to prevent or treat infectious disease and cancer.
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PMID:Building better vaccines: how apoptotic cell death can induce inflammation and activate innate and adaptive immunity. 1100 65

The concept of differential regulation of certain adhesion molecules on different cell subsets and their relevance to cell functions has emerged in recent years. The initial event in bone remodeling is an increase in osteoclastic bone resorption and cell adhesion between osteoclastic precursors and bone marrow stromal cells or osteoblasts is known to commit the osteoclast development. Here, we show that human osteoblasts can be divided into two subsets based on the expression of the intercellular adhesion molecule (ICAM)-1; ICAM-1+ osteoblasts highly adhered to monocytes, including osteoclast precursors, produced osteoclast differentiation factor (ODF), and induced multinuclear osteoclast-like cell formation. Anti-ODF monoclonal antibody (mAb) did not inhibit the adhesion of monocytes to osteoblastic cells, whereas anti-leukocyte function-associated antigen (LFA)-1, a receptor for ICAM-1, mAb blocked the adhesion. We thereby propose that the higher affinity adhesion via LFA-1/ICAM-1 is prerequisite for efficient function of membrane-bound ODF during osteoclast maturation. The functional characteristics of ICAM-1+ osteoblasts were emphasized further by cell cycle regulation, as manifested by (i) up-regulation of p53 and p21, (ii) reduction of activity of cyclin-dependent kinase (cdk) 6, (iii) underphosphorylation of retinoblastoma protein, (iv) increased Fas but reduced bcl-2 expression, and (v) majority of cells remained at G0/G1 phase. Furthermore, ICAM-1+ osteoblasts were induced by interleukin-1beta (IL-1beta). Taken together, we propose that the differentiation of osteoblasts to ICAM-1+ subpopulation by inflammatory cytokines plays an important role in osteoporosis, which is observed in patients with chronic inflammation, because ICAM-1+ osteoblasts can bias bone turnover to bone resorption, committing osteoclast maturation through cell adhesion with its precursor, and the majority of ICAM-1+ osteoblasts arrested at G0/G1 phase. Such regulation of cell cycle arrest also is an important determinant of the life span of cells in bone in which continuous bone remodeling maintains its homeostasis.
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PMID:Intercellular adhesion molecule 1 discriminates functionally different populations of human osteoblasts: characteristic involvement of cell cycle regulators. 1102 43

Recent studies have shown an up-regulation of the Fas/Fas ligand system in inflammatory myopathies. In myositis, however, the major Fas-mediated cytotoxicity which activates caspases bypasses apoptosis. We therefore evaluated the expression of proteins promoting cell survival, such as bcl-2, bcl-x(l) and cyclin-dependent kinase inhibitors, on muscle biopsies from 14 patients with polymyositis, dermatomyositis, inclusion body myositis and HIV-associated myositis. Our data demonstrate that inflammatory cells are immunoreactive for bcl-x(l), p16 and p57, three apoptosis-preventing proteins. Hence, we assume that these proteins might protect T cells from apoptotic nuclear changes. Our results could explain the non-self-limiting nature of inflammatory myopathies.
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PMID:T-cell anti-apoptotic mechanisms in inflammatory myopathies. 1106 32


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