Modes of inhibition of protein kinase C by triphenylacrylonitrile antiestrogens.
Protein kinase C (PKC) I (gamma), II (beta) and III (alpha) subspecies' activities are inhibited by three triphenylacrylonitrile (TPE) antiestrogens at micromolar concentrations. TPE 1 (having a p-hydroxy and a p-diethylaminoethoxy group on the 3-, and 3'- phenyl rings respectively) and TPE 2 (having a p-diethylaminoethoxy group on both the 3-, and 3'- phenyl rings) are competitive with the mechanism of activation by phosphatidylserine (PS). TPE 3 (having p-hydroxy groups on each of the three phenyl rings) is non-competitive with PS and inhibits the Ca2+- and PS-independent phosphorylation of protamine sulfate by PKC subspecies. This evidence suggests that PKC activity can be inhibited by different routes depending on the TPE structure: diethylaminoethoxy side chain-substituted TPEs (TPE 1 and 2) interact with PS as well as with the regulatory domain, whereas the trihydroxylated derivative (TPE 3) inhibits the enzyme by interacting with the catalytically active site.
Department of Biochemistry, Kobe University School of Medicine, Japan.
E
E
Bignon
K
K
Ogita
A
A
Kishimoto
J
J
Gilbert
J
J
Abecassis
J F
JF
Miquel
Y
Y
Nishizuka
D000181:Acrylonitrile / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D009570:Nitriles / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000494:pharmacology; D010743:Phospholipids / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
D004965:Estrogen Antagonists; D007527:Isoenzymes; D009570:Nitriles; D010718:Phosphatidylserines; D010743:Phospholipids; C040969:2,3,3-triphenylacrylonitrile; D011493:Protein Kinase C; D000181:Acrylonitrile; D002118:Calcium