Mechanism of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands.
Cells and tissue preparations specifically bind the phorbol ester tumor promoters. The agreement in structure-activity relationships between binding and biological response strongly argues that these binding sites function as phorbol ester receptors. Upon subcellular fractionation, the phorbol ester binding activity is particulate. In addition, a phorbol ester apo-receptor can be detected in cytosol which requires phospholipids for reconstitution. This apo-receptor appears to correspond to protein kinase C. Diacylglycerols, the probable natural activators of protein kinase C, competitively inhibit phorbol ester binding, consistent with their being the postulated endogenous phorbol ester analogs. In certain systems, heterogeneity of phorbol ester binding is found. An outstanding issue therefore is whether protein kinase C is the phorbol ester receptor or whether it is only the most abundant class of receptor. Although this question remains unresolved, we can demonstrate heterogeneity of phorbol ester binding by reconstitution of apo-receptor into a heterogeneous lipid environment.
D000818:Animals; D001923:Brain Chemistry; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000494:pharmacology; D002352:Carrier Proteins; D004075:Diglycerides / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced*; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000378:metabolism / Q000633:toxicity*; D010704:Phorbols / Q000633:toxicity*; D010743:Phospholipids / Q000032:analysis; D011493:Protein Kinase C; D011494:Protein Kinases / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis*; D011955:Receptors, Drug; D014316:Tritium
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D004075:Diglycerides; D010703:Phorbol Esters; D010704:Phorbols; D010743:Phospholipids; D011956:Receptors, Cell Surface; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D014316:Tritium; D015240:Phorbol 12,13-Dibutyrate; D011494:Protein Kinases; D011493:Protein Kinase C; D002118:Calcium; C013965:diolein