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)

Incubation of human lymphoblastoid cell extracts in the presence of cAMP and ATP produces changes in the chromatographic pattern of terminal transferase activity separated on phosphocellulose columns. Incubation of high molecular weight and low molecular weight preparations of calf thymus terminal transferase with the catalytic subunit of beef cardiac muscle cAMP-dependent protein kinase and [gamma-32P]ATP result in phosphorylation of the 58,000-dalton form of the enzyme and no other lower molecular weight terminal peptides. These results, taken with our earlier results on tissue proteolysis of terminal transferase to lower molecular weight, active forms (Chang, L. M. S., Plevani, P., and Bollum, F. J. (1982) J. Biol. Chem. 257, 5700-5706), resolve the heterogeneity observed with various preparations of the enzyme.
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PMID:Cyclic AMP-dependent phosphorylation of terminal deoxynucleotidyl transferase. 628 27

The nucleoside analogue cordycepin (3'-deoxyadenosine), when protected against ADA deamination, is specifically cytotoxic for TdT-positive leukemia cells. Cordycepin-treated, ADA-inhibited, TdT-positive cells undergo the classic changes associated with drug-induced apoptosis: reduction in cell volume, chromatin clumping, membrane blebbing, and 180-bp multimer DNA laddering on agarose gels. In common with the apoptosis seen in normal TdT-positive thymocytes, following exposure to various agents, apoptosis induced by cordycepin in TdT-positive leukemia cells was associated with increased protein kinase A (PK-A) activity. Unlike thymocyte apoptosis however, no elevation in cAMP levels was seen preceding the rise in PK-A activity. Ex vivo we show that cordycepin monophosphate can activate PK-A as efficiently as cAMP. On this basis we speculate that cordycepin monophosphate in TdT-positive cells may be able to activate PK-A in place of cAMP, and that PK-A may phosphorylate TdT, augmenting its activity as an endonuclease. In cell-free experiments, the activity of recombinant TdT as an endonuclease digesting supercoiled plasmid DNA into linear fragments was dramatically increased following phosphorylation of TdT by PK-A. A role for TdT as an apoptotic endonuclease in TdT-positive leukemia cells following cordycepin exposure is now the subject of on-going work.
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PMID:Induction of apoptosis by cordycepin in ADA-inhibited TdT-positive leukemia cells. 866 37

Manipulation of signal transduction pathways has been increasingly used to modulate tumor growth. We have investigated the effects of up-regulation of the cAMP/protein kinase A (PKA) pathway in cell lines and primary cultures of malignant gliomas. The malignant glioma cell line A-172 was treated with agonistic cAMP analogs dibutyryl cyclic AMP (dcAMP) and 8-bromo-cyclic AMP (8-Br-cAMP), an adenylate cyclase activator (forskolin), and a phosphodiesterase inhibitor (3-isobutyl-1-methyl-xanthene [IBMX]). Proliferation was determined by 3H-thymidine assay. Differentiation was measured by morphologic changes, glial fibrillary acidic protein (GFAP) content, and invasion potential. Apoptosis was measured quantitatively by the TUNEL method, which labels DNA fragments using terminal transferase. Agonistic cAMP analogs, forskolin, and IBMX were found to decrease proliferation in A-172 cells after 24 hours. Treatment with 8-Br-cAMP for 24 hours caused an increase in GFAP and decrease in invasion. Apoptosis was induced after 48 hours in the presence of synergistic cAMP analogs for the Type II PKA isozyme, but not Type I PKA isozyme. Activation of PKA by increasing cAMP levels (forskolin, IBMX) or directly by cAMP analogs correlated with decreased proliferation, increased differentiation, and induction of apoptosis in A-172 cells. Modulation of the cAMP/PKA pathway may thus represent a possible target site for treating malignant gliomas.
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PMID:Up-regulation of the cAMP/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas. 948 14

Previously we reported that phorbol ester, a protein kinase C (PKC) activator, exhibits a unique pattern of potentiation of nitric oxide (NO)-related apoptosis in HL-60 human promyelocytic leukemia cells. Here we show that elevation of intracellular cAMP could protect HL-60 cells from NO- or NO plus PMA-induced DNA damage. Exposure of cells to sodium nitroprusside (SNP; 0.5 to 4 mM), a NO-generating agent, induced apoptotic cell death as monitored by morphological means, gel electrophoresis, and in situ TdT-apoptosis assay. However, concomitant incubation of the cells with DB-cAMP markedly inhibited SNP-induced apoptotic cell death in a dose-dependent manner. Similar results were obtained with other commonly used cAMP analogs such as CPT-cAMP and 8-C1-cAMP and the intracellular cAMP-elevating agent such as forskolin. In contrast, pretreatment of HL-60 cells with H89 or KT5720, which are known to inhibit cAMP-dependent protein kinase (PKA), abolished the protective effect of cAMP analogs and forskolin on SNP-induced apoptosis. Synergism between SNP and phorbol ester to induce apoptosis was also inhibited by prior treatment of HL-60 cells with DB-cAMP or forskolin. The effect of DB-cAMP in maintaining cell viability was not associated with the onset of G0/G1 cell cycle arrest. In addition, neither dimethyl sulfoxide nor retinoic acid (which produce granulocyte differentiation) could produce cAMP effect. Under the same conditions, DB-cAMP also inhibited NO- or NO plus phorbol ester-induced apoptosis in another transformed cell line, U-937 cells. Taken together, these findings suggest that exposure of HL-60 cells to cAMP analogs renders them more resistant to NO-induced DNA damage and further suggest the existence of specific down-modulatory mechanisms related to NO-induced apoptotic DNA fragmentation.
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PMID:Cyclic adenosine monophosphate inhibits nitric oxide-induced apoptosis in human leukemic HL-60 cells. 957 15

Partial loss of the radiation G2/M checkpoint is thought to be an early event in cell immortalization. One of the attributes of immortalized cell lines is an increase in susceptibility to induction of genomic instability by clastogenic agents. Recently we have shown that in irradiated HeLa cells cell cycle delays in late S and G2 lead to overaccumulation of cyclin B1 and that enhanced intracellular levels of this positive regulator of the cell cycle is correlated with cyclin-dependent kinase activation, spontaneous premature chromosome condensation and subsequent mitotic catastrophe occurring following irradiation. Previous studies have shown that spontaneous premature chromosome condensation and mitotic catastrophe are independent of apoptosis. This report shows that 40 h following X-irradiation of HeLa S3 cells, and subsequent to mitotic catastrophe, DNA strand breaks appear which are chemically distinct from those initially produced by ionizing radiation. This delayed damage is recognized by terminal transferase and thus involves generation of free 3'-OH ends. Pulse field gel electrophoresis analysis of DNA size distributions shows that DNA fragments of approximately 40 kbp and smaller are produced. As strand breaks produced as a direct result of irradiation are generally repaired within a few hours after exposure to X-rays at the doses used, these results describe a novel mechanism for generation of DNA damage occurring a day or more following irradiation. These results may be pertinent to the understanding of mechanisms underlying the delayed lethal effects of irradiation and may provide an initiating mechanism for radiation-induced genomic instability.
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PMID:Delayed DNA damage associated with mitotic catastrophe following X-irradiation of HeLa S3 cells. 971 69

We immunohistochemically analyzed the expression of double-stranded RNA-dependent protein kinase (PKR) using a monoclonal antibody, 71/10. Test samples included 64 human liver biopsies and 25 liver sections of rats inoculated with diethylnitrosamine. The PKR signals in human fatty livers and normal rat livers were minimum. Scoring signal intensity from 0-4, the average scores of chronic active (14 cases) and chronic persistent (6 cases) hepatitis associated with hepatitis virus C (HCV) were 2.8 and 2.0, respectively (P = 0.038). The stained cells were significantly more abundant in the periportal than centrilobular regions for both chronic active and persistent hepatitis (P < 0.001 each). The average score of liver cirrhosis associated with HCV was 1.9. Those scores of well-, moderately, and poorly differentiated hepatocellular carcinomas associated with HCV were 3.4, 2.1, and 0.3, respectively (P < 0.001 for each pair). Those scores of well- and poorly differentiated carcinomas associated with hepatitis virus B were 2.3 and 0.0, respectively (P < 0.001). The average score of rat carcinomas induced by diethylnitrosamine was 1.9. Morphologically, nuclei of the vast majority of PKR-positive cells looked not apoptotic. The ratio of PKR-positive cells to apoptotic cells by terminal transferase-mediated dUTP nick end labeling method was approximately 20 in hepatitis, and over 100 in well-differentiated carcinoma.
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PMID:Aberrant expression of double-stranded RNA-dependent protein kinase in hepatocytes of chronic hepatitis and differentiated hepatocellular carcinoma. 976 75

Two membrane-permeable and RNase-resistant antisense poly-2'-O-(2,4-dinitrophenyl)-oligoribonucleotides (poly-DNP-RNAs) have been synthesized as inhibitors of human breast cancer, with nucleotide sequences complementary to the genes of RIalpha subunit of protein kinase A (RIalpha/PKA) and erbB-2, respectively. Both compounds inhibit the proliferation of SK-Br-3 breast cancer cells in culture above the concentration of 10 microg/ml, but have no effect on nontumorigenic MCF-10A breast cells. These antisense inhibitors also block the cell colony formation in methylcellulose medium, whereas the control poly-DNP-RNA with either random or sense sequence has no effect. RT-PCR data show that the antisense inhibition decreases the concentration of the mRNA. TdT-mediated dUTP nick-end labeling (TUNEL) fluorescence assay indicates that the targeted antisense inhibition by poly-DNP-RNAs leads to apoptosis of SK-Br-3 cells but does not affect nontumorigenic MCF-10A cells. The control poly-DNP-RNAs with random or sense nucleotide sequence are completely inactive.
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PMID:Specific inhibition of breast cancer cells by antisense poly-DNP-oligoribonucleotides and targeted apoptosis. 1010 Jul 55

Inactivation of protein kinase Cdelta (PKCdelta) is associated with resistance to terminal cell death in epidermal tumor cells, suggesting that activation of PKCdelta in normal epidermis may be a component of a cell death pathway. To test this hypothesis, we constructed an adenovirus vector carrying an epitope-tagged PKCdelta under a cytomegalovirus promoter to overexpress PKCdelta in normal and neoplastic keratinocytes. While PKCdelta overexpression was detected by immunoblotting in keratinocytes, the expression level of other PKC isozymes, including PKCalpha, PKCepsilon, PKCzeta, and PKCeta, did not change. Calcium-independent PKC-specific kinase activity increased after infection of keratinocytes with the PKCdelta adenovirus. Activation of PKCdelta by 12-O-tetradecanoylphorbol-13-acetate (TPA) at a nanomolar concentration was lethal to normal and neoplastic mouse and human keratinocytes overexpressing PKCdelta. Lethality was inhibited by PKC selective inhibitors, GF109203X and Ro-32-0432. TPA-induced cell death was apoptotic as evidenced by morphological criteria, TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay, DNA fragmentation, and increased caspase activity. Subcellular fractionation indicated that PKCdelta translocated to a mitochondrial enriched fraction after TPA activation, and this finding was confirmed by confocal microscopy of cells expressing a transfected PKCdelta-green fluorescent protein fusion protein. Furthermore, activation of PKCdelta in keratinocytes altered mitochondrial membrane potential, as indicated by rhodamine-123 fluorescence. Mitochondrial inhibitors, rotenone and antimycin A, reduced TPA-induced cell death in PKCdelta-overexpressing keratinocytes. These results indicate that PKCdelta can initiate a death pathway in keratinocytes that involves direct interaction with mitochondria and alterations of mitochondrial function.
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PMID:Protein kinase Cdelta targets mitochondria, alters mitochondrial membrane potential, and induces apoptosis in normal and neoplastic keratinocytes when overexpressed by an adenoviral vector. 1056 79

Infection with either Streptococcus sanguis or Streptococcus pneumoniae type 25 causes acute pneumonitis in rats. Pneumonia caused by S. sanguis resolves over the course of 8 d, whereas pneumonia caused by S. pneumoniae type 25 progresses to fibrosis. To examine the role of apoptosis in these models, we performed assays with the terminal deoxynucleotidyltransferase-uridine nucleotide end-labeling technique on tissue sections from rat lungs at various times, and quantified the results with image analysis. Apoptosis was a feature of both the acute and resolving stages of pneumonia. The pattern and extent of apoptosis were similar in both models during the acute stage, and the number of apoptotic nuclei increased in both models through 4 d after infection. Although there were differences in the cellular pattern of apoptosis after 2 d and 4 d of infection, the extent of apoptosis was the same in both models. After 8 d, major differences were observed. In the resolving model, apoptosis was limited primarily to an abscess in the base of the lung. In the nonresolving model, apoptosis was persistent. We also found that cyclin-dependent kinase-5 expression is upregulated during apoptosis induced by bacterial infection. These data indicate that the location and timing of apoptosis may determine whether pneumonia resolves or progresses to fibrosis.
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PMID:Differential patterns of apoptosis in resolving and nonresolving bacterial pneumonia. 1085 86

The ubiquitin proteasome system is responsible for the proteolysis of important cell cycle and apoptosis-regulatory proteins. In this paper we report that the dipeptidyl proteasome inhibitor, phthalimide-(CH2)8CH-(cyclopentyl) CO-Arg(NO2)-Leu-H (CEP1612), induces apoptosis and inhibits tumor growth of the human lung cancer cell line A-549 in an in vivo model. In cultured A-549 cells, CEP1612 treatment results in accumulation of two proteasome natural substrates, the cyclin-dependent kinase inhibitors p21WAF1 and p27KIP1, indicating its ability to inhibit proteasome activity in intact cells. Furthermore, CEP1612 induces apoptosis as evident by caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Treatment of A-549 tumor-bearing nude mice with CEP1612 (10 mg/kg/day, i.p. for 31 days) resulted in massive induction of apoptosis and significant (68%; P < 0.05) tumor growth inhibition, as shown by terminal deoxynucleotidyltransferase-mediated UTP end labeling. Furthermore, immunostaining of tumor specimens demonstrated in vivo accumulation of p21WAF1 and p27KIP1 after CEP1612 treatment. The results suggest that CEP1612 is a promising candidate for further development as an anticancer drug and demonstrate the feasibility of using proteasome inhibitors as novel antitumor agents.
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PMID:CEP1612, a dipeptidyl proteasome inhibitor, induces p21WAF1 and p27KIP1 expression and apoptosis and inhibits the growth of the human lung adenocarcinoma A-549 in nude mice. 1124 20


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