1. Effect of tamoxifen, a nonsteroidal antiestrogen, on phospholipid/calcium-dependent protein kinase and phosphorylation of its endogenous substrate proteins from the rat brain and ovary.
- Author
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Su HD, Mazzei GJ, Vogler WR, and Kuo JF
- Subjects
- Animals, Autoradiography, Brain enzymology, Diethylstilbestrol pharmacology, Estradiol pharmacology, Female, In Vitro Techniques, Myosin-Light-Chain Kinase, Ovary enzymology, Phosphorylation, Protein Kinase C antagonists & inhibitors, Protein Kinases metabolism, Rats, Brain drug effects, Ovary drug effects, Protein Kinase C metabolism, Tamoxifen pharmacology
- Abstract
Antiestrogens (tamoxifen, clomiphene and nafoxidine) were found to inhibit phospholipid/Ca2+-dependent protein kinase (PL/Ca-PK, or protein kinase C), whereas estrogens (estradiol and diethylstilbesterol) and the weakly estrogenic chlorotrianisene were inactive. Kinetic analysis indicated that the antiestrogens inhibited PL/Ca-PK competitively with respect to phosphatidylserine (Ki = 16-27 microM), but non-competitively with Ca2+ (Ki = 14-30 microM). Tamoxifen, but not diethylstilbesterol, also inhibited the phospholipid/Ca2+-dependent phosphorylation of various endogenous proteins from the total, solubilized fraction of the rat brain and ovary. Myosin light chain kinase, a calmodulin/Ca2+-dependent class of protein kinase, was similarly inhibited by tamoxifen; the drug, however, was without effect on cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It is suggested that PL/Ca-PK, by virtue of the hydrophobic interactions required for the enzyme activation, may represent a potential site of action for the lipophilic antiestrogens, in addition to the commonly recognized intracellular estrogen receptors.
- Published
- 1985
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