Diacylglycerols mimic phorbol diester induction of leukemic cell differentiation.
Activation of cellular protein kinase C appears to be involved in the mechanism by which phorbol diesters induce differentiation of human myeloid leukemia cells (HL-60). Protein kinase C is thought to be physiologically activated by diacylglycerol derived from receptor-mediated phosphatidylinositol hydrolysis. sn-1,2-diacylglycerols with short saturated acyl side chains (C4-C10) were synthesized and found to be potent activators of protein kinase C partially purified from HL-60 cells. These diacylglycerols were also competitive inhibitors of [3H]phorbol dibutyrate binding to the soluble phorbol diester receptor. The most potent diacylglycerol, sn-1,2-dioctanoylglycerol, displaced greater than 90% of [3H]phorbol dibutyrate from the phorbol diester receptor of intact HL-60 cells. Because of probable cellular metabolism of sn-1,2-dioctanoylglycerol, hourly doses were required to maintain persistent occupancy of the phorbol diester binding site. Treatment of HL-60 cells with either phorbol 12-myristate 13-acetate or sn-1,2-dioctanoylglycerol produced identical phosphoprotein changes. Finally, sn-1,2-dioctanoylglycerol induced differentiation of the HL-60 cells into cells with morphologic characteristics of macrophages. Substitution of the hydroxyl group at position 3 with a hydrogen, chloro, or sulfhydryl moiety inactivated sn-1,2-dioctanoylglycerol. These data strengthen the hypothesis that protein kinase C activation plays a role in macrophage differentiation.
Ebeling
J G
JG
Vandenbark
G R
GR
Kuhn
L J
LJ
Ganong
B R
BR
Bell
R M
RM
Niedel
J E
JE
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004075:Diglycerides / Q000494:pharmacology*; D004789:Enzyme Activation; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000378:metabolism / Q000494:pharmacology*; D010704:Phorbols / Q000494:pharmacology*; D011493:Protein Kinase C; D011494:Protein Kinases / Q000378:metabolism; D011955:Receptors, Drug; D011971:Receptors, Immunologic / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D004075:Diglycerides; D005989:Glycerides; D010703:Phorbol Esters; D010704:Phorbols; D011955:Receptors, Drug; D011971:Receptors, Immunologic; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D015240:Phorbol 12,13-Dibutyrate; D011494:Protein Kinases; D011493:Protein Kinase C