Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of cultured rat aortic smooth muscle cells (A-10) with activators of cyclic nucleotides resulted in transiently increased activity of extractable topoisomerase I or topoisomerase II. ANF, which induces cGMP accumulation, potentiated camptothecin-induced, topoisomerase I linked DNA strand breakage and increased the specific activity of extractable topoisomerase I (maximum activity 5-15 min after treatment), but had no effect on topoisomerase II activity. These effects are similar to those reported for AVP and phorbol esters, activators of protein kinase C. Forskolin and isoproterenol, which induce cAMP accumulation, activated extractable topoisomerase II (maximum 5-15 min after treatment), but not topoisomerase I. Permeable cyclic nucleotide analogs dBcAMP and 8BrcGMP selectively activated extractable topoisomerase II and topoisomerase I activities, respectively. Activation of topoisomerase I by either AVP or PdBu was attenuated by cotreatment with 8BrcGMP or dBcAMP, and activation of topoisomerase II by dBcAMP was attenuated by cotreatment with AVP or PdBU, suggesting that elements of the protein kinase C and the cyclic nucleotide linked signal-transduction pathways can interact to modify nuclear enzymic activity. IBMX, which elevates intracellular cAMP and cGMP, increased the extractable activities of both topoisomerase I and topoisomerase II. Thus, topoisomerase activity in cells may be governed in part by cyclic nucleotide levels.
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PMID:Regulation of topoisomerase I and II activities by cyclic nucleotide- and phospholipid-dependent protein kinases. Effects of interactions between the two transduction pathways. 166 30

We have recently demonstrated that certain camptothecin derivatives are effective agents in the treatment of human tumor xenografts in nude mice. While camptothecin and its derivatives are recognized as inhibitors of topoisomerase I, little is known about the effects of these agents on specific gene expression, particularly genes involved in growth control. The c-jun early response gene codes for a leucine zipper transcription factor. The present studies demonstrate that 20(S)-camptothecin, 9-amino-20(S)-camptothecin, and 9-nitro-20(S)-camptothecin inhibit the growth of human U-937 myeloid leukemia cells and induce expression of the c-jun gene. c-jun transcripts were increased at 3 h and reached a maximum at 6 h of drug exposure. We also demonstrate that the induction of c-jun gene expression by these agents occurs at the transcriptional level. H7, a nonselective inhibitor of protein kinase C, completely blocked c-jun expression in 20(S)-camptothecin-treated cells, while another protein kinase inhibitor, HA1004, had no detectable effect. Similar findings were obtained for other leucine zipper encoding genes, including jun-B. These results suggest that 20(S)-camptothecin, 9-amino-20(S)-camptothecin, and 9-nitro-20(S)-camptothecin activate a cellular response involving the induction of early response genes. Finally, we demonstrate that induction of c-jun expression occurs in association with internucleosomal DNA fragmentation, a characteristic of programmed cell death.
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PMID:Camptothecin and its derivatives induce expression of the c-jun protooncogene in human myeloid leukemia cells. 174 37

U937 human monoblast cells incubated with leukotriene D4 (LTD4) rapidly released arachidonic acid metabolites into the culture medium. Release was suppressed by the high-affinity LTD4 receptor antagonist SK&F 104353. Arachidonic acid release induced by LTD4 has been linked to a rapid induction of gene expression, and the propagation of the receptor binding signal is probably associated with enzymes that regulate gene expression. We have studied the participation of DNA topoisomerase I in LTD4 signal transduction. LTD4-specific release of arachidonic acid metabolites was inhibited (60-80%) by the topoisomerase I inhibitor camptothecin. LTD4 increased protein-linked DNA strand breakage induced by camptothecin in U937 cells; this enhancement was prevented by coincubation of the cells with LTD4 plus the receptor antagonist SK&F 104353. In addition, LTD4 produced a rapid transient increase in extractable topoisomerase I activity, which was maximum within the first 10 min after addition of LTD4 to the culture medium. Incubation of cultures for greater than 10 min with LTD4 before the addition of camptothecin resulted in no enhancement of camptothecin-induced DNA strand breakage, consistent with a reversal of topoisomerase I activation. Staurosporine, an inhibitor of protein kinase C, blocked LTD4-induced arachidonic acid release and attenuated the effect of LTD4 on camptothecin-induced DNA strand breakage. These results are consistent with the view that the regulation of topoisomerase I activity is involved in the propagation of LTD4-mediated signals in U937 cells.
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PMID:Transient activation of topoisomerase I in leukotriene D4 signal transduction in human cells. 215 78

The influence of mammalian DNA topoisomerase I phosphorylation on enzyme activity has been investigated. Dephosphorylation by calf intestine alkaline phosphatase abolished the DNA relaxing activity of DNA topoisomerase I and the sensitivity of the enzyme to its specific inhibitor, camptothecin. DNA topoisomerase I could be reactivated by incubation with purified protein kinase C. DNA topoisomerase I was then able to relax supercoiled DNA processively, like the native enzyme, and to cleave 32P-end-labeled SV40 DNA fragments at the same sequences as the native enzyme in the presence of camptothecin. These results show that active DNA topoisomerase I is a phosphoprotein and suggest a possible regulatory role of protein kinase on topoisomerase I activity and on its sensitivity to camptothecin.
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PMID:Phosphorylation of mammalian DNA topoisomerase I and activation by protein kinase C. 216 Sep 79

Studies were conducted to determine the possible involvement of DNA topoisomerase II (Topo II) in the induction of differentiation in two human promyelocytic HL-60 leukemia cell variants that are either susceptible or resistant to differentiation induced by phorbol-12-myristate-13-acetate (PMA), a protein kinase C activator. The acquisition of maturation markers and changes in the activity, level, and phosphorylation of Topo II were determined after treatment with either novobiocin, a Topo II inhibitor, or PMA. Novobiocin at 50-150 microM induced differentiation in the HL-205 cells but not in the HL-525 cells, although both cell types were equally susceptible to novobiocin-evoked cytotoxicity. In both cell types, novobiocin induced similar reductions in topoisomerase I activity but different reductions in Topo II activity. Treatment with novobiocin at 150 microM for 6 h or at 2 mM for 30 min resulted in a 4-fold or higher reduction in Topo II activity in the differentiation-susceptible HL-205 cells but not in the differentiation-resistant HL-525 cells. A differential response in Topo II activity was also observed after treatment with PMA. The novobiocin-evoked decrease in Topo II activity seems to be due to an enhanced enzyme proteolysis, whereas the PMA-elicited decrease in Topo II activity is associated with an increase in Topo II phosphorylation. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine, which is an inhibitor of protein kinases, including protein kinase C, diminished the novobiocin-elicited proteolysis of Topo II and the PMA-induced Topo II phosphorylation, as well as the decrease in Topo II activity and the acquisition of differentiation markers induced by either novobiocin or PMA. These results suggest that induction of differentiation in HL-60 cells by novobiocin or PMA is associated with a reduction in Topo II activity, mediated directly or indirectly by a protein kinase(s), perhaps protein kinase C.
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PMID:Novobiocin- and phorbol-12-myristate-13-acetate-induced differentiation of human leukemia cells associated with a reduction in topoisomerase II activity. 253 41

Exposure of human skin fibroblasts to phorbol 12-myristate 13-acetate (PMA) results in a transient increase in the level of topoisomerase I mRNA. A maximal increase (about 10-fold) in the level of topoisomerase I mRNA was observed 3 h after adding 200 nM PMA, but a decrease to the basal level was observed within 12 h of PMA treatment. The lowest PMA concentration to give an observable induction of topoisomerase I gene expression was found to be 20 nM. In addition, the induction of topoisomerase I gene expression by 20 nM PMA pulse treatment for 10 min followed by incubation for an additional 3 h attained the same level of induction seen with 3 h of continuous exposure to 20 nM PMA. This observation suggests that once the signal for protein kinase C activation is transduced, continuous exposure to PMA is not necessary for the maximal effect. To gain insight into the mechanism by which PMA stimulates topoisomerase I gene expression, cells were treated with PMA, cycloheximide, and actinomycin D, either alone or in various combinations. The results show that actinomycin D, but not cycloheximide, specifically abolishes the stimulatory effect of PMA, suggesting that PMA affects topoisomerase I gene expression at the transcriptional level.
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PMID:Phorbol ester transiently increases topoisomerase I mRNA levels in human skin fibroblasts. 254 41

The induction of mammalian cell proliferation requires the expression of a specific set of genes. Tumor promoters stimulate cell growth by activating the Ca2+ and phospholipid-dependent protein kinase, protein kinase C (PKC). DNA topoisomerase I, a nuclear enzyme involved in transcription, was phosphorylated by activated PKC in vitro. Phosphorylation by PKC stimulated the DNA relaxation activity of topoisomerase I two- to three-fold. Therefore, DNA topoisomerase I is a substrate for PKC-mediated activation by phosphorylation and may serve as a nuclear target of mitogenic signals generated by tumor promoters in vivo.
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PMID:Protein kinase C phosphorylates DNA topoisomerase I. 255 45

There is significant evidence to suggest that protein kinase C and DNA topoisomerases are functionally linked in signal transduction pathways. Much of this is based on the observation that phosphorylation of topoisomerase II by protein kinase C may lead to its activation in vitro and that inhibitors of topoisomerase II block phorbol diester-induced differentiation in HL-60 cells. In the present study, the activities of the DNA topoisomerases I and II have been quantitated to examine their regulation in phorbol diester-treated HL-60 cells undergoing differentiation. The activity of topoisomerase I increased rapidly after treatment with phorbol myristate acetate (PMA); it increased maximally (150% of control activity) at 3 hr post-treatment and remained elevated for at least 24 hr. Conversely, from the onset of exposure to PMA through 12 hr, there was no measurable alteration in topoisomerase II activity in PMA-treated cells. Moreover, there was a measurable decrease in topoisomerase II activity at the later time points, a result that occurred concomitantly with the loss of proliferative potential in differentiating HL-60 cells. Similar results were obtained when the activities of both enzymes were measured in nuclear extracts. The apparent increase in topoisomerase I activity was not due to an increase in the mass of the enzyme after PMA treatment, as measured by both western blotting and by the formation of camptothecin-dependent, topoisomerase I-DNA complexes. Taken together, these data suggest that the activities of the topoisomerases I and II may have been regulated independently in PMA-treated HL-60 cells, that the activity of topoisomerase II was not increased under conditions in which protein kinase C was activated in vivo, and that an increase in the activity of topoisomerase I may have had a role in the mechanism through which HL-60 cells underwent monocytic maturation in response to phorbol diesters.
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PMID:Rapid increase in the activity of DNA topoisomerase I, but not topoisomerase II, in HL-60 promyelocytic leukemia cells treated with a phorbol diester. 256 36

Oxidants can act at multiple stages of carcinogenesis. While they cause genetic damage and are cytotoxic, they also activate cellular pathways which alter gene expression, growth, and differentiation. Certain pathways used by polypeptide growth factors and hormones are also activated by oxidants. For example, oxidants stimulate the phosphorylation of the ribosomal subunit S6, the phosphotransferase activity of protein kinase C, and induce its translocation to the plasma membrane. On the genomic level, oxidants increase the transcription of the growth-competence-related protooncogenes c-fos and c-myc. In addition to these growth factor-type reactions, oxidants induce pathways which are unique to them. Poly ADP-ribosylation of chromosomal proteins is of particular relevance to oxidant carcinogenesis. It represents an epigenetic consequence of DNA-breakage. Both histones and nonhistone proteins are poly ADP-ribosylated in response to oxidants. Among non-histones, ADPR-transferase, topoisomerase I, and the fos oncoprotein were identified as acceptors. Inhibition of poly ADP-ribosylation suppressed the oxidant-induced transcription of c-fos. Since fos oncoprotein serves as a transcriptional regulator, we speculate that its poly ADP-ribosylation and that of other chromosomal proteins plays a role in the modulation of gene expression in response to oxidative stress.
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PMID:Mechanisms of action of oxidant carcinogens. 269 47

Recent years have seen the introduction into clinical trials of new classes of chemotherapeutic agents which are derived from natural sources and have novel mechanisms of action. Examples of some of these newer classes of agents are presented here to illustrate both the opportunities they represent with respect to cancer treatment applications and the challenges which they represent from the clinical development perspective. Cumulatively the problems encountered with the development of the agents described are representative of the spectrum of issues encountered in the development of natural products, ranging from initial characterization and purification through the difficulties encountered in obtaining sufficient quantities of material for preclinical studies and then ultimately for clinical trials. Since these agents have unique mechanisms of action and are often exquisitely dose- and schedule-dependent in pre-clinical studies, they represent significant complexities with respect to determining the optimal regimen of administration clinically. The particular agents chosen for description here represent the spectrum of natural source-derived materials as well as mechanisms of action. The taxanes are derived from tree sources and interfere with the mitotic spindle apparatus; the camptothecins, while also derived from trees, appear to exert their activity through interactions with topoisomerase I. Bryostatin, derived from a marine animal, has powerful effects on protein kinase C (PKC), and therefore affects signal transduction pathways within cells. Fumagillin analogs appear to exhibit their important antitumor activity not through a direct effect on cancer cells but rather through effects on the tumor neovasculature. Taken as a whole, the spectrum of agents and activities described here confirms the continued importance of natural products in current anticancer agent development and reflects the complexities involved in this area of clinical research.
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PMID:Clinical development of anticancer agents from natural products. 790 43


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