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.
Bignon
E
E
Department of Biochemistry, Kobe University School of Medicine, Japan.
Ogita
K
K
Kishimoto
A
A
Gilbert
J
J
Abecassis
J
J
Miquel
J F
JF
Nishizuka
Y
Y
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