title: Farnesyl thiotriazole, a potent neutrophil agonist and structurally novel activator of protein kinase C.
abstract: Farnesylcysteine derivatives can initiate or inhibit superoxide (O2-) release in neutrophils. The mechanism by which one of these derivatives, farnesyl thiotriazole (FTT), initiates O2- release in neutrophils is the subject of this paper. Treatment of guinea pig neutrophils with FTT results in the rapid release of O2- by a route shown to be independent of the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP) receptor. The signal transduction pathway utilized by the chemoattractant fMLP is generally accepted as the paradigm for receptor-mediated stimulation of O2- production. Antagonists of fMLP had no effect on FTT-induced O2- release, and pretreatment of neutrophils with fMLP had no effect on the ability of FTT to trigger further O2- generation. In fact, FTT behaves like a typical protein kinase C (PKC) activator. It promotes phosphorylation of the 47-kDa subunit of the NADH oxidase complex (p47-phox) in neutrophils, and this phosphorylation is specifically blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an antagonist of PKC. FTT is also shown to activate PKC in vitro in a specific and saturable fashion. FTT is approximately equipotent with (S)-diolein, a physiologically relevant activator of this kinase. FTT represents a new, and quite novel, structure for a PKC activator. PKC activators include diglycerides and the structurally diverse tumor promoters.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: B A
authors.initials: BA
authors.lastname: Gilbert
authors.forename: Y H
authors.initials: YH
authors.lastname: Lim
authors.forename: J
authors.initials: J
authors.lastname: Ding
authors.forename: J A
authors.initials: JA
authors.lastname: Badwey
authors.forename: R R
authors.initials: RR
authors.lastname: Rando
mesh_terms: D000818:Animals; D004075:Diglycerides / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004075:Diglycerides; D010710:Phosphates; D010750:Phosphoproteins; D014230:Triazoles; D013481:Superoxides; C092766:farnesylthiotriazole; D005204:Farnesol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate