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Vol. 303, Issue 1, 82-88, October 2002
TC3 Cells by Novel Inhibitors of Protein Isoprenylation
Department of Pharmaceutical Sciences, Wayne State University, and
The majority of low molecular weight G proteins undergoes a series of
post-translational modification steps, e.g., isoprenylation, at their
C-terminal cysteine, which seem to be critical for the transport of the
modified proteins to the membrane sites for interaction with their
respective effector proteins. Using lovastatin, an inhibitor of
mevalonic acid, and hence, isoprenoid biosynthesis, we demonstrated
previously that protein isoprenylation is critical for physiological
insulin secretion from normal rat islets. Herein, we used more
selective synthetic inhibitors of protein prenylation to examine their
effects on glucose- and calcium-mediated insulin secretion from 
Cell Biochemistry Research Laboratory, John D. Dingell VA Medical
Center, Detroit, Michigan (R.A., H.-Q.C., M.T., A.K.); and Department
of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy
and Pharmacal Sciences, Purdue University, West Lafayette, Indiana
(R.G.)
TC3
cells. Both 3-allyl- and vinylfarnesols, which inhibit and/or
modulate protein farnesyl transferases, significantly (80-95%)
inhibited glucose- and KCl-stimulated insulin secretion from these
cells. In a similar manner, the allyl and vinyl forms of
geranylgeraniol, reagents targeted toward protein geranylation, attenuated insulin secretion elicited by glucose and KCl. Furthermore, manumycin A, a natural inhibitor of protein farnesylation, and geranylgeranyl transferase inhibitor-2147 (GGTI-2147), a
peptidomimetic inhibitor of protein geranylgeranylation, also inhibited
glucose- and KCl-induced insulin secretion to comparable degrees.
Treatment of TC3 cells with either 3-vinylfarnesol or 3-vinyl
geranylgeraniol resulted in accumulation of unprenylated proteins in
the cytosolic fraction. These data further support our original
formulation that inhibition of isoprenylation of small molecular weight
G proteins might impede their interaction with their putative
effectors, which may be required for physiological insulin secretion.
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