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)

A member of the mitogen-activated protein (MAP) kinase family, Jun N-terminal kinase (JNK), has been implicated in regulating apoptosis in various cell types. We have investigated the requirement for another type of MAP kinase, extracellular signal-regulated protein kinase (ERK) in activation-induced cell death (AICD) of T cells. AICD is the process by which recently activated T cells undergo apoptosis when restimulated through the T-cell antigen receptor. Here we show that both JNK and ERK are activated rapidly upon T-cell receptor (TCR) ligation prior to the onset of AICD. A chemical inhibitor of ERK activation, PD 098059, inhibits ERK activation and apoptosis, while JNK activation is not inhibited. This suggests that JNK activation is not sufficient for apoptosis. TCR cross-linking induces expression of the apoptosis-inducing factor, Fas ligand (FasL), and its expression correlates with ERK activation. In addition, apoptosis induced by direct ligation of the Fas receptor by anti-Fas antibody is not associated with ERK activation and is not inhibited by PD 098059. These data suggest that ERK activation is an early event during T-cell apoptosis induced by antigen-receptor ligation, and is not involved in apoptosis per se but in the expression of FasL. MAP kinase family members may be similarly involved in inducing apoptosis signals in other cell types.
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PMID:Role of mitogen-activated protein kinases in activation-induced apoptosis of T cells. 1044 11

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

Natural products regulate cell growth in response to oncogene activation that induces cell cycle arrest and apoptosis in tumor cell lines. We investigated the mechanisms of caspase activation in human malignant melanoma, A375-S2 cells, by the natural product shikonin, which was isolated from the plant Lithospermum erythrorhizon SIEB. et ZUCC. Shikonin inhibited cell growth in a time- and dose-dependent manner, which might be mediated through up-regulation of p53 and down-regulation of cyclin-dependent protein kinase 4. Caspase activation was detected in shikonin-induced cell apoptosis, which involved in a post-mitochondrial caspase-9-dependent pathway. Decreased Bcl-2 protein levels and increased Bax protein levels were positively correlated with elevated expression of p53 protein. Apoptosis-inducing factor, another apoptotic protein of mitochondria, partially contributed to shikonin-induced release of cytochrome c. Taken together, shikonin-induced DNA damage activates p53 and caspase-9 pathways.
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PMID:p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells. 1497 55

Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl(+) human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34(+) cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of Bcr-Abl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and B-Raf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl(+) leukemias, including those resistant to STI571.
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PMID:Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change. 1562 78

Allicin, the major component of Garlic (Allium sativum) was examined for the ability to induce apoptosis and the mechanism of the induction of apoptosis in human epithelial carcinoma cells. Allicin inhibited cell growth and induced apoptosis in gastric epithelial cells. Treatment with allicin resulted in morphological changes, DNA fragmentation, hypodiploid DNA contents and the translocation of Bax to mitochondria. The release of cytochrome c from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was observed in allicin-treated cells. However, pretreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), a broad spectrum of caspase inhibitor, could not rescue apoptotic cells from allicin toxicity. Coincidently, caspase-3 activation and cleavage of PARP were not detected. In addition, caspase independent apoptosis-inducing factor (AIF) was released from mitochondria after treatment with allicin. After pre-incubation of cells with the protein kinase A (PKA) inhibitor H-89, allicin was not capable of inducing an increase of the rate of apoptosis with affecting the expression levels of Bax and AIF. These data demonstrate that allicin induces a caspase-independent apoptotic pathway mediated by mitochondrial release of AIF and PKA appears to be involved in allicin-induced apoptosis in gastric epithelial cells.
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PMID:Caspase-independent cell death by allicin in human epithelial carcinoma cells: involvement of PKA. 3052 59

Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamide and sodium butyrate) were examined in human leukemia cells (U937 and HL-60) ectopically expressing Bcl-2/Bcl-x(L) and in primary AML cells. Coadministration of flavopiridol with HDAC inhibitors synergistically potentiated mitochondrial damage (cytochrome c, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI, and apoptosis-inducing factor release), caspase activation, poly(ADP-ribose) polymerase degradation, and cell death in both wild type and Bcl-2- or Bcl-x(L)-overexpressing cells and induced a pronounced loss of clonogenicity. In contrast, Bcl-2 and Bcl-x(L) largely blocked these events in cells exposed to the cytotoxic agent 1-beta-d-arabinofuranosylcytosine (ara-C). Enforced expression of dominant-negative Fas-associated death domain failed to protect cells from the flavopiridol/histone deacetylase inhibitor (HDACI) regimen, arguing against the involvement of the receptor pathway in lethality. Ectopic expression of a phosphorylation loop-deleted Bcl-2 or Bcl-2 lacking the serine(70) phosphorylation site, which dramatically protected cells from ara-C lethality, delayed but did not prevent flavopiridol/HDAC inhibitor-induced mitochondrial injury, cell death, or loss of clonogenicity. Ectopic expression of Bcl-2 or Bcl-x(L) was also unable to prevent the flavopiridol/HDACI regimen from inducing a conformational change in and mitochondrial translocation of Bax, and it did not attenuate Bax dimerization. As a whole, these findings indicate that in contrast to certain conventional cytotoxic agents such as ara-C, overexpression of Bcl-2 or Bcl-x(L) are largely ineffective in preventing perturbations in Bax, mitochondrial injury, and cell death in human leukemia cells subjected to simultaneous CDK and HDAC inhibition. They also raise the possibility that a strategy combining CDK and HDAC inhibitors may be effective against drug-resistant leukemia cells overexpressing Bcl-2 or Bcl-x(L).
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PMID:Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. 3082 53

Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 micromol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.
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PMID:Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. 1627 99

We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.
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PMID:OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. 1662 74

The ubiquitous vacuolar H(+)-ATPase, a multisubunit proton pump, is essential for intraorganellar acidification. Disruption of its function leads to disturbances of organelle function and cell death. Here, we report that overexpression of the B2 subunit of the H(+)-ATPase inhibits apoptosis. This antiapoptotic effect is not mediated by an increase in H(+)-ATPase activity but through activation of the Ras-mitogen-activated protein kinase (MAPK)-signaling pathway that results in the serine phosphorylation of Bad at residues 112 and 155. Increased Bad phosphorylation reduces its translocation to mitochondria, limits the release of mitochondrial cytochrome c and apoptosis-inducing factor and increases the resistance of the B2 overexpressing cells to apoptosis. Screening experiments of kinase inhibitors, including inhibitors of cAMP-activated protein kinase, protein kinase C, protein kinase B, (MAPK/extracellular signal-regulated (ERK) kinase) MEK and Ste-MEK1(13), a cell permeable ERK activation inhibitor peptide, revealed that the B2 subunit of H(+)-ATPase acts upstream of MEK activation in the MEK/ERK pathway to ameliorate apoptosis.
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PMID:A novel cellular survival factor--the B2 subunit of vacuolar H+-ATPase inhibits apoptosis. 1671 Mar 59

Based on the perturbation of its expression in human cancers and on its involvement in transformation and tumorigenesis, protein kinase CK2 has recently attracted attention as a potential therapeutic target. To assess the value of CK2 as a target for antiproliferative strategies, we have initiated a program aiming to develop inhibitors targeting specifically the regulatory CK2beta subunit. Here, we use a two-hybrid approach to isolate from combinatorial libraries, peptide aptamers that specifically interact with CK2beta. One of these (P1), which has significant sequence homology to the cytomegalovirus IE2 protein, binds with high affinity to the N-terminal domain of CK2beta without disrupting the formation of the CK2 holoenzyme. Expression of green fluorescent protein (GFP)-P1 in different mammalian cell lines activates p53 phosphorylation on serine 15, induces an upregulation of p21 and the release of the Cyt-C and apoptosis-inducing factor proapoptotic proteins triggering caspase-dependent and caspase-independent apoptosis. GFP-P1-induced apoptosis is associated with a p53-dependent pathway as cell death was abrogated in p53 knocked out cells. In summary, our data show that genetically selected peptide aptamers that specifically target CK2beta can induce apoptosis in mammalian cells through the recruitment of a p53-dependent apoptosis pathway. They also emphasize the critical role of CK2beta for cell survival and might allow the design of novel proapoptotic agents targeting this protein.
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PMID:p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2. 1675 1


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