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Lovastatin inhibits T-cell antigen receptor signaling independent of its
effects on ras
F Goldman, RJ Hohl, J Crabtree, K Lewis-Tibesar and G Koretzky
Department of Pediatrics, University of Iowa Hospital and Clinics, Iowa
City 52242, USA.
Lovastatin, a cholesterol-lowering drug, has antiproliferative properties
that may be related to its inhibition of protein isoprenylation. We
examined the effects of lovastatin on signal transduction via the T-cell
antigen receptor (TCR). Lovastatin inhibited both proximal and distal
TCR-mediated signaling events in a time- and concentration-dependent manner
in the human Jurkat T-cell line. Upregulation of CD69 surface expression
after TCR stimulation was blocked by lovastatin, although no inhibition of
phorbol ester-induced CD69 expression was noted. Proximal TCR-mediated
signaling events, including intracellular calcium mobilization, inositol
phosphate production, and tyrosine phosphorylation of phospholipase
Cgamma1, were similarly inhibited by lovastatin, although global protein
tyrosine kinase activity remained intact. In a Jurkat variant transfected
with the human type-1 muscarinic receptor, lovastatin also inhibited TCR-
mediated calcium mobilization and inositol phosphate production but failed
to affect muscarinic receptor-induced responses. Lovastatin, at similar
doses, also disrupted post-translational processing of ras and inhibited
ras-dependent signals, including phosphorylation and activation of
mitogen-associated protein kinase after TCR stimulation. These findings
suggest that the antiproliferative properties of lovastatin may be
independent of ras and could result from uncoupling protein tyrosine
kinases from distinct signal transduction pathways.
Volume 88,
Issue 12,
pp. 4611-4619,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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