Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60.
Phorbol esters bind to and activate a calcium phospholipid-dependent protein kinase (C kinase). Some researchers believe that activation of C kinase is necessary for the induction of phorbol ester biologic effects. Our research indicates that bryostatin, a macrocyclic lactone that binds to the phorbol ester receptor in human polymorphonuclear leukocytes, also binds to this receptor in the human promyelocytic leukemia cell line, HL-60. Bryostatin activates partially purified C kinase from HL-60 cells in vitro, and when applied to HL-60 cells in vivo, it decreases measurable cytoplasmic C kinase activity. Unlike the phorbol esters, bryostatin is unable to induce a macrophage-like differentiation of HL-60 cells; however, bryostatin, in a dose-dependent fashion, blocks phorbol ester-induced differentiation of HL-60 cells and, if applied within 48 hr of phorbol esters, halts further differentiation. These results suggest that activation of the C kinase by some agents is not sufficient for induction of HL-60 cell differentiation and imply that some of the biologic effects of phorbol esters may occur through a more complex mechanism than previously thought.
Kraft
A S
AS
Smith
J B
JB
Berkow
R L
RL
D001667:Binding, Competitive; D054713:Bryostatins; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute; D018942:Macrolides; D010703:Phorbol Esters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011955:Receptors, Drug; D011971:Receptors, Immunologic / Q000378:metabolism
D054713:Bryostatins; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D007783:Lactones; D018942:Macrolides; D010703:Phorbol Esters; D011955:Receptors, Drug; D011971:Receptors, Immunologic; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; C046785:bryostatin 1; D011493:Protein Kinase C