Regulation of topoisomerase I and II activities by cyclic nucleotide- and phospholipid-dependent protein kinases. Effects of interactions between the two transduction pathways.
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.
Mattern
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MR
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Nambi
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P
Bartus
J O
JO
Mirabelli
C K
CK
Crooke
S T
ST
Johnson
R K
RK
D000818:Animals; D002457:Cell Extracts / Q000302:isolation & purification; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D010743:Phospholipids / Q000502:physiology*; D011493:Protein Kinase C / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D002457:Cell Extracts; D010743:Phospholipids; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D006152:Cyclic GMP