Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the...

We have recently presented evidence indicating that during biosynthesis of squalene from farnesyl pyrophosphate by rat liver microsomes, 1 hydrogen atom attached to carbon 1 of 1 of the 2 precursor molecules condensing to squalene was exchanged for a hydride ion derived from reduced triphosphopyridine nucleotide (1). This conclusion was drawn from the observations, (a) that during synthesis of ...

Using oligonucleotide-mediated 'loop-in' mutagenesis strategies in M13, a heat-inducible ubiquitin (Ub) gene was extended by sequences coding for the C-terminal 11 amino acids of Ha-RAS. The resulting gene was transformed into AR13 and production of the Ub-peptide extension was induced by heat treatment. After one-step purification, the fusion protein (Ub-cRAS) was used as a substrate for farne...

The association of mutant forms of Ras protein with a variety of human cancers has stimulated intense interest in therapies based on inhibiting oncogenic Ras signaling. Attachment of Ras proteins to the plasma membrane is required for effective Ras signaling and is initiated by the enzyme farnesyl protein transferase. We found that in the presence of potent farnesyl protein transferase inhibito...

The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of calcium fluorescent as...

In order to investigate the substrate binding feature of undecaprenyl diphosphate synthase from Micrococcus luteus B-P 26 with respect to farnesyl diphosphate and a reaction intermediate, (Z,E,E)-geranylgeranyl diphosphate, we examined the reactivity of artificial substrate analogs, 3-desmethyl farnesyl diphosphate and 3-desmethyl Z-geranylgeranyl diphosphate, which lack the methyl group at the...

Human tumor cell lines that are sensitive to the effects of farnesyl transferase inhibitors accumulate in G(2) --> M (except for cells with an activated Ha-ras that accumulate in G(1)). A search for CAAX box proteins from Swiss-Prot revealed more than 300 peptides. Of these, the centromeric proteins CENP-E and CENP-F are preferentially expressed during mitosis and are implicated as mediators of...

Active Ras contributes to the malignant phenotype of glioblastoma multiforme. Recent studies showed that the Ras inhibitor farnesyl thiosalicylic acid downregulates the transcription factor hypoxia-inducible factor-1alpha, causing shutdown of glycolysis in U87 glioblastoma cells. Farnesyl thiosalicylic acid also inhibited the growth of U87 cells. The way in which Ras inhibition affects U87 cell...

An inhibition in the conversion of mevalonate to cholesterol has been demonstrated in liver of cholesterol-fed rats by both in vitro and in vivo methods. Synthesis decreased to 30% of the control value after 1 week and 20% after 1 month on a 1% cholesterol diet. After a year, synthesis from mevalonate was almost completely inhibited. The rate of conversion of squalene to cholesterol was not con...

Ras protein is involved in a signal transduction cascade in cell growth, and cluster formation of H-Ras and human galectin-1 (Gal-1) complex is considered to be crucial to achieve its physiological roles. It is considered that the complex is formed through interactions between Gal-1 and the farnesyl group (farnesyl-dependent model), post-translationally modified to the C-terminal Cys, of H-Ras....