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)

Cell cycle arrest in G2 phase is a common response to a variety of DNA-damaging agents. The coupling between DNA damage and G2 arrest was studied in synchronized HeLa cells using camptothecin, a highly specific inhibitor of topoisomerase I that damages DNA through the formation of reversible topoisomerase I-DNA cleavable complexes. Brief camptothecin treatment of early S-phase HeLa cells caused arrest at G2 phase and abolished the activation of p34cdc2 protein kinase. Both tyrosine dephosphorylation of p34cdc2 and cyclin B accumulation were altered. These cell cycle-dependent changes were not observed when DNA replication was inhibited by aphidicolin during the brief camptothecin treatment. Our results suggest that to produce G2 arrest, active DNA synthesis is required at the time of camptothecin treatment, as was previously shown for camptothecin-induced cytotoxicity. Furthermore, our results suggest that the interaction of the replication fork with DNA damage may ultimately trigger altered regulation of p34cdc2/cyclin B, leading to cell cycle arrest at the G2 phase.
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PMID:The involvement of active DNA synthesis in camptothecin-induced G2 arrest: altered regulation of p34cdc2/cyclin B. 131

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

1. Calf thymus DNA-topoisomerase I has been isolated, in an improved preparation, nearly to SDS-PAGE homogeneity, as a single major protein (100 kDa). 2. In vitro labeling experiments, which employed the purified enzyme [gamma-32P]ATP and N II protein kinase, also showed that the calf thymus topoisomerase I became phosphorylated. 3. Phosphorylation was accompanied by an increase in topoisomerase I activity. 4. Phosphoaminoacid analysis indicated that only serine residues became phosphorylated. 5. Tryptic peptides mapping, by HV electrophoresis, identified five major [32P]peptides. This number is higher than that reported for topoisomerase I from Novikoff hepatoma cells. 6. Separation of each spot, by reverse phase HPLC, resulted in their elution at fractions 1, 2, 3, 4 and 5 with 9, 11, 16, 27 and 28% acetonitrile, respectively. 7. Isolated phosphopeptides will be subjected to sequencing, to DNA-binding and transcription regulation tests; then, it will be speculated whether type N II protein kinase may contribute to the physiological regulation of DNA topoisomerase I activity from calf thymus, as well.
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PMID:Phosphorylation sites for type N II protein kinase in DNA-topoisomerase I from calf thymus. 216 38

Monoclonal anti-Sm antibody, a specificity directed against a constituent of nuclear ribonucleoprotein and considered to be a marker for systemic lupus erythematosus (SLE), was tested for its ability to react with four other rheumatic disease antigens of known enzymatic activity. No binding of the antibody was observed in radioimmunoassays with immobilized protein kinase NII, poly(A) polymerase, or topoisomerase I. In contrast, anti-Sm antibody did react with RNA polymerase I. Under conditions of antibody excess, anti-Sm was determined to bind RNA polymerase I on an equimolar basis, indicating that the polymerase possesses a single epitope recognized by the anti-Sm antibody. Addition of the anti-Sm antibody to in vitro transcription reactions resulted in inhibition of RNA polymerase I activity but had no effect on the reaction catalyzed by RNA polymerase II. When the subunits of RNA polymerase I were separated by polyacrylamide gel electrophoresis under denaturing conditions and incorporated individually into the radioimmunoassay, anti-Sm antibody bound only to the sixth polymerase polypeptide (Mr, 21,000). These data establish an immunological relationship between two important rheumatic disease antigens and help explain the apparent diversity of the autoimmune response in murine and human SLE.
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PMID:Monoclonal antibody against the lupus antigen Sm cross-reacts with RNA polymerase I. 249 8

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

Our previous studies have shown that the regulatory subunits of the type II form of cAMP-dependent protein kinase (RII) present in soluble extract of immature rat ovaries elute from diethylaminoethyl-cellulose as three separate peaks of activity, based on their association with the catalytic subunit (C) of this enzyme, as R2IIC2, an apparent R2IIC, and R2II. Based upon the existence of ovarian RII in three different subunit arrangements, the large amount of C subunit-free R2II in this tissue, and a previous report which indicated that RII exhibited intrinsic topoisomerase I activity, we determined whether DNA topoisomerase I activity was associated with any of these molecular complexes of the ovarian RII subunits. Cyclic AMP-binding activities in soluble extracts of preovulatory follicle-enriched immature rat ovaries were separated by diethylaminoethyl-cellulose chromatography and sucrose density gradient centrifugation. Topoisomerase I activity cosedimented with the apparent R2IIC and R2II obtained from sucrose gradients but was not detected in fractions containing R2IIC2. Upon cAMP affinity purification of the RII derived from fractions containing R2IIC2, R2IIC, and R2II, respectively, no topoisomerase I activity could be detected in any fraction. Phosphorylation of the affinity purified RIIs by the C subunit of beef heart cAMP-dependent protein kinase did not alter this result. These data indicate that none of the RII subunits in soluble extracts of preovulatory follicle-enriched ovaries exhibit intrinsic topoisomerase I activity.
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PMID:Separation of the complexes formed between the regulatory and catalytic subunits of cyclic adenosine monophosphate-dependent protein kinase and topoisomerase I activity in preovulatory follicle-enriched immature rat ovaries. 254 53

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

Transcription of ribosomal RNA genes is generally accepted to correlate with cell growth. Using primary cultures of adult bovine aortic endothelial (ABAE) cells, we have shown that transcription of rDNA in confluent cells falls to 5% of the transcription level in growing cells. Protein kinase NII appears to be a limiting factor to promote rDNA transcription in isolated nuclei of confluent cells. Protein kinase NII was detected by immunocytochemistry in the cytoplasm, nuclei and nucleoli of growing cells while it was no longer present in nucleoli of confluent cells. The kinase activity, in isolated nuclei, was estimated by endogenous phosphorylation of a specific substrate, nucleolin. A 10% residual activity was present in confluent cell nuclei compared to growing cell nuclei. Concomitantly, the transcription 'in vitro' of rDNA in the corresponding nuclei was also highly reduced (by 85%). Addition of exogenous protein kinase NII to confluent cell nuclei induced a strong increase in the phosphorylation of specific proteins including nucleolin. In parallel, the transcription of rDNA was increased by a factor of 5, to nearly the level observed in nuclei prepared from growing cells. These data suggest that, in confluent cells, factors necessary for rDNA transcription machinery are present but inactive in the nucleolus and that the phosphorylation of one or several of these factors (nucleolin, topoisomerase I,...) by protein kinase NII is a key event in the regulation of rDNA transcription.
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PMID:Protein kinase NII and the regulation of rDNA transcription in mammalian cells. 278 Feb 90

The cAMP-containing phosphoform of the regulatory subunit (RII) of type II cAMP-dependent protein kinase from rat liver has been reported to have intrinsic DNA topoisomerase I activity. We found that highly purified RII preparations from eight different sources, including rat liver, contained no detectable topoisomerase I activity. Topoisomerase I exhibited an overlapping peak of activity with RII when rat liver extracts were fractionated by diethylaminoethyl-cellulose chromatography. Topoisomerase I activity was separated from RII by subsequent cAMP affinity chromatography. The results indicate that the regulatory subunit of cAMP-dependent protein kinase does not contain intrinsic topoisomerase I activity.
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PMID:Separation of topoisomerase I activity from the regulatory subunit of type II cyclic adenosine monophosphate-dependent protein kinase. 283 63

Changes in phosphorylation modulate the activity of topoisomerase I in vitro. Specifically, enzymatic activity is stimulated by phosphorylation with a purified protein kinase (casein kinase type II). The purpose of this study was to compare the sites that are phosphorylated in vitro by casein kinase type II with the site(s) phosphorylated in vivo in rapidly growing Novikoff hepatoma cells. Topoisomerase I labeled in vitro was characterized by three major tryptic phosphopeptides (I-III). Separation of these peptides by a C18-reverse phase h.p.l.c. column resulted in their elution at fractions 18 (I), 27 (II) and 44 (III) with 17%, 22.5% and 33% acetonitrile, respectively. In contrast, only one major phosphopeptide was identified by h.p.l.c. in topoisomerase I labeled in vivo. This phosphopeptide eluted at fraction 18 corresponding to the elution properties of phosphopeptide I labeled in vitro. It also co-migrated with tryptic phosphopeptide I when subjected to high-voltage electrophoresis on thin-layer cellulose plates. Preliminary experiments suggest that phosphorylation occurs at a serine residue six amino acids from the N-terminus of the peptide. These data indicate that topoisomerase I is phosphorylated in vivo and in vitro within the same tryptic peptide and suggest that topoisomerase I is phosphorylated in vivo by casein kinase II.
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PMID:Topoisomerase I phosphorylation in vitro and in rapidly growing Novikoff hepatoma cells. 299 65


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