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
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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.