Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether RhoA isoprenylation (geranylgeranylation) is required for agonist-induced actin cytoskeleton reorganization (measured by an increase in the filamentous F- to monomeric G-actin ratio), human airway smooth muscle cells were treated for 72 h with inhibitors of geranylgeranyltransferase I. Geranylgeranyltransferase inhibitor (GGTI)-2147 or -286 pretreatment completely blocked the increase in the F- to G-actin fluorescence ratio when cells were stimulated with lysophosphatidic acid (LPA), endothelin, or carbachol. In contrast, LPA or endothelin induced actin cytoskeletal reorganization in cells treated with farnesyltransferase inhibitor (FTI)-277 to inactivate Ras. Forskolin-induced adenylyl cyclase activity was inhibited by carbachol in GGTI-2147-pretreated cells, demonstrating that the effect of geranylgeranyltransferase I inhibition on stress fiber formation was not due to uncoupling of signaling between the heterotrimeric G(i) protein (the Ggamma subunit is isoprenylated) and distal effectors. These results demonstrate that selective GGTIs can inhibit agonist-induced actin reorganization.
Am J Physiol Lung Cell Mol Physiol 2001 Oct
PMID:Inhibition of geranylgeranylation blocks agonist-induced actin reorganization in human airway smooth muscle cells. 1155 86

RhoB is an endosomal small GTPase that is implicated in the response to growth factors, genotoxic stress, and farnesyltransferase inhibitors. To gain insight into its physiological functions we examined the consequences of homozygous gene deletion in the mouse. Loss of RhoB did not adversely affect mouse development, fertility, or wound healing. However, embryo fibroblasts cultured in vitro exhibited a defect in motility, suggesting that RhoB has a role in this process that is conditional on cell stress. Neoplastic transformation by adenovirus E1A and mutant Ras yielded differences in cell attachment and spreading that were not apparent in primary cells. In addition, transformed -/- cells displayed altered actin and proliferative responses to transforming growth factor beta. A negative modifier role in transformation was suggested by the increased susceptibility of -/- mice to 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis and by the increased efficiency of intraperitoneal tumor formation by -/- cells. Our findings suggest that RhoB is a negative regulator of integrin and growth factor signals that are involved in neoplastic transformation and possibly other stress or disease states.
Mol Cell Biol 2001 Oct
PMID:RhoB is dispensable for mouse development, but it modifies susceptibility to tumor formation as well as cell adhesion and growth factor signaling in transformed cells. 1156 74

Over the past few years, the number of identified inborn errors of cholesterol biosynthesis has increased significantly. The first inborn error of cholesterol biosynthesis to be characterized, in the mid 1980s, was mevalonic aciduria. In 1993, Irons et al. ( 1 ) (M. Irons, E. R. Elias, G. Salen, G. S. Tint, and A. K. Batta, Lancet 341:1414, 1993) reported that Smith-Lemli-Opitz syndrome, a classic autosomal recessive malformation syndrome, was due to an inborn error of cholesterol biosynthesis. This was the first inborn error of postsqualene cholesterol biosynthesis to be identified, and subsequently additional inborn errors of postsqualene cholesterol biosynthesis have been characterized to various extent. To date, eight inborn errors of cholesterol metabolism have been described in human patients or in mutant mice. The enzymatic steps impaired in these inborn errors of metabolism include mevolonate kinase (mevalonic aciduria as well as hyperimmunoglobulinemia D and periodic fever syndrome), squalene synthase (Ss-/- mouse), 3beta-hydroxysteroid Delta14-reductase (hydrops-ectopic calcification-moth-eaten skeletal dysplasia), 3beta-hydroxysteroid dehydrogenase (CHILD syndrome, bare patches mouse, and striated mouse), 3beta-hydroxysteroid Delta8,Delta7-isomerase (X-linked dominant chondrodysplasia punctata type 2, CHILD syndrome, and tattered mouse), 3beta-hydroxysteroid Delta24-reductase (desmosterolosis) and 3beta-hydroxysteroid Delta7-reductase (RSH/Smith-Lemli-Opitz syndrome and Dhcr7-/- mouse). Identification of the genetic and biochemical defects which give rise to these syndromes has provided the first step in understanding the pathophysiological processes which underlie these malformation syndromes.
Mol Genet Metab
PMID:Genetic disorders of cholesterol biosynthesis in mice and humans. 1159 8

Protein farnesylation, catalyzed by protein farnesyltransferase, plays important roles in the membrane association and protein-protein interaction of a number of eukaryotic proteins. Recent development of farnesyltransferase inhibitors (FTIs) has led to further insight into the biological significance of farnesylation in cancer cells. A number of reports point to the dramatic effects FTIs exert on cancer cells. In addition to inhibiting anchorage-independent growth, FTIs cause changes in the cell cycle either at the G1/S or at the G2/M phase. Furthermore, induction of apoptosis by FTIs has been reported. FTIs also affects the actin cytoskeleton and cell morphology. This review summarizes these reports and discusses implications for farnesylated proteins responsible for these FTI effects.
Cell Mol Life Sci 2001 Oct
PMID:Protein farnesylation in mammalian cells: effects of farnesyltransferase inhibitors on cancer cells. 1170 90

After isoprenylation, the Ras proteins and other CAAX proteins undergo two additional enzymatic modifications-endoproteolytic release of the last three amino acids of the protein by the protease Rce1 and methylation of the carboxyl-terminal isoprenylcysteine by the methyltransferase Icmt. This postisoprenylation processing is thought to be important for the association of Ras proteins with membranes. Blocking postisoprenylation processing, by inhibiting Rce1, has been suggested as a potential approach for retarding cell growth and blocking cellular transformation. The objective of this study was to develop a cell culture system for addressing these issues. We generated mice with a conditional Rce1 allele (Rce1(flox)) and produced Rce1(flox/flox) fibroblasts. Cre-mediated excision of Rce1 (thereby producing Rce1(Delta/Delta) fibroblasts) eliminated Ras endoproteolytic processing and methylation and caused a partial mislocalization of truncated K-Ras and H-Ras fusion proteins within cells. Rce1(Delta/Delta) fibroblasts grew more slowly than Rce1(flox/flox) fibroblasts. The excision of Rce1 also reduced Ras-induced transformation, as judged by the growth of colonies in soft agar. The excision of Rce1 from a Rce1(flox/flox) skin carcinoma cell line also significantly retarded the growth of cells, and this effect was exaggerated by cotreatment of the cells with a farnesyltransferase inhibitor. These studies support the idea that interference with postisoprenylation processing retards cell growth, limits Ras-induced transformation, and sensitizes tumor cells to a farnesyltransferase inhibitor.
Mol Cell Biol 2002 Jan
PMID:Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. 1173 32

We isolated and artificially expressed a cDNA clone of the Capsicum annuum squalene synthase (CASS) gene to elucidate the pattern of alternatively regulated two-branch point enzymes. The 1,674-bp CASS cDNA contained an open reading frame of 411 amino acids, yielding a predicted molecular mass of about 45 kDa. A deduced amino acid sequence comparison to other squalene syntheses showed identities with Nicotiana tabacum (91%), Nicotiana benthamiana (90%), Arabidopsis thaliana (79%), and rats (40%). The artificially expressed soluble form of the CASS enzyme was identified by the enzyme activity that converted FPP to squalene and by SDS-PAGE. A Southern blot analysis indicated that at least two copies of the squalene synthase gene exist in the hot pepper genome. In hot pepper, the regulation of the branch point enzymes, squalene synthase and sesquiterpene cyclase was investigated in the UV-challenged leaves of Capsicum annuum. The transcript level and enzyme activity of the CASS were slightly reduced by UV. However, those of the CASC were rapidly induced within 24 h and slowly decreased thereafter.
Mol Cells 2002 Jun 30
PMID:Cloning and expression of squalene synthase cDNA from hot pepper (Capsicum annuum L.). 1213 84

Ionizing radiation (1-5 Gy) activates the epidermal growth factor receptor (EGFR), a major effector of the p42/44 mitogen-activated protein kinase (MAPK) pathway. MAPK and its downstream effector, p90 ribosomal S6 kinase (p90RSK), phosphorylate transcription factors involved in cell proliferation. To establish the role of the EGFR/MAPK pathway in radiation-induced transcription factor activation, MDA-MB-231 human breast carcinoma cells were examined using specific inhibitors of signaling pathways. Gel-shift analysis revealed three different profile groups: 1) transcription factors that responded to both radiation (2 Gy) and epidermal growth factor (EGF) (CREB, Egr, Ets, and Stat3); 2) factors that responded to radiation, but not EGF (C/EBP and Stat1); and 3) those that did not respond significantly to either radiation or EGF (AP-1 and Myc). Within groups 1 and 2, a two- to fivefold maximum stimulation of binding activity was observed at 30-60 min after irradiation. Interestingly, only transcription factors that responded to EGF had radiation responses significantly inhibited by the EGFR tyrosine kinase inhibitor, AG1478; these responses were also abrogated by farnesyltransferase inhibitor (FTI) or PD98059, inhibitors of Ras and MEK1/2, respectively. Moreover, radiation-induced increases in CREB and p90RSK phosphorylation and activation of Stat3 and Egr-1 reporter constructs by radiation were all abolished by AG1478. These data demonstrate a distinct radiation response profile at the transcriptional level that is dependent on enhanced EGFR/Ras/MAPK signaling.
Mol Biol Cell 2002 Jul
PMID:Epidermal growth factor receptor dependence of radiation-induced transcription factor activation in human breast carcinoma cells. 1213 64

Because our previous studies indicated that squalestatin 1 treatment induces CYP2B expression in primary cultures of rat hepatocytes as a direct consequence of squalene synthase inhibition, we investigated possible underlying mechanisms. Cotransfection of cultured Sprague-Dawley male rat hepatocytes with each of the three sterol regulatory element binding protein (SREBP) transcription factors failed to induce luciferase expression from a squalestatin 1-responsive CYP2B1 reporter plasmid. Squalestatin 1 treatment of primary hepatocyte cultures from male Wistar-Kyoto rats produced a greater induction of CYP2B mRNA than occurred in cultures from female rats, consistent with the previously demonstrated response dimorphism that has been attributed to differences in constitutive androstane receptor (CAR) levels. Cotransfection of female Wistar-Kyoto rat hepatocyte cultures with plasmid expressing either mouse or rat CAR restored squalestatin 1-inducible CYP2B1-reporter expression. Cotransfection of Sprague-Dawley rat hepatocyte cultures with plasmid expressing rat CAR lacking the C-terminal AF-2 subdomain inhibited squalestatin 1-inducible CYP2B1-reporter expression. Squalestatin 1-mediated CYP2B mRNA induction in rat hepatocyte cultures was completely abolished by pretreatment with the 3-hydroxymethyl-3-glutaryl CoA reductase inhibitor pravastatin and was rescued by mevalonate supplementation, whereas phenobarbital-mediated induction was unaffected by these treatments. Finally, direct addition of trans,trans-farnesol to the culture medium caused the rapid induction of CYP2B mRNA. These results indicate that squalestatin 1 treatment induces CYP2B expression, not by inhibiting sterol synthesis and activating SREBPs, but by evoking the accumulation of an endogenous isoprenoid and activating CAR.
Mol Pharmacol 2002 Nov
PMID:Squalestatin 1-inducible expression of rat CYP2B: evidence that an endogenous isoprenoid is an activator of the constitutive androstane receptor. 1239 Dec 82

Farnesyltransferase inhibitors (FTIs) block the growth of tumor cells in vitro and in vivo with minimal toxicity toward normal cells. In general, inhibition of protein farnesylation results in G0/G1 cell cycle block, G2/M cell cycle arrest, or has no effect on cell cycle progression. One aspect of FTI biology that is poorly understood is the ability of these drugs to induce cancer cell growth arrest at the G2/M phase of cell cycle. In the present study, we investigated the effects of the farnesyltransferase inhibitor FTI-277 on two human liver cancer cell lines, HepG2 and Huh7. Treatment of these cells with FTI-277 inhibited Ras farnesylation in a dose-dependent manner. Both HepG2 and Huh7 cell growth was inhibited by FTI-277 and cells accumulated at the G2/M phase of the cell cycle. In HepG2 and Huh7 cells, FTI-277 induced an up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) without affecting the cellular levels of p53 and p21(Waf1). This event correlated with reduced activity of the cyclin-dependent kinase 2 and cyclin-dependent kinase 1. Moreover, increased expression of Bcl-2 protein was observed in HepG2 and Huh7 cells treated with FTI-277, and this was coincidental with reduced association between Raf-1 and Bcl-2. Finally, transient transfection of a dominant-negative Ras allele induced Bcl-2 expression and reduced Bcl-2/Raf-1 association demonstrating a requirement for Ras. Taken together, these findings show that increased expression of p27(Kip1) and Bcl-2 is concomitant with altered association between Ras, Raf-1 and Bcl-2 and suggest that this is responsible for the growth-inhibitory properties of FTI-277.
Mol Pharmacol 2003 Jan
PMID:Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines. 1248 48

Loss of axonal contact characterizes Schwann cells in benign and malignant peripheral nerve sheath tumors (MPNST) from neurofibromatosis type 1 (NF1) patients. Tumor Schwann cells demonstrate NF1 mutations, elevated Ras activity, and aberrant epidermal growth factor receptor (EGFR) expression. Using cDNA microarrays, we found that brain lipid binding protein (BLBP) is elevated in an EGFR-positive subpopulation of Nf1 mutant mouse Schwann cells (Nf1(-/-) TXF) that grows away from axons; BLBP expression was not affected by farnesyltransferase inhibitor, an inhibitor of H-Ras. BLBP was also detected in EGFR-positive cell lines derived from Nf1:p53 double mutant mice and human MPNST. BLBP expression was induced in normal Schwann cells following transfection with EGFR but not H-Ras12V. Furthermore, EGFR-mediated BLBP expression was not inhibited by dominant-negative H-Ras, indicating that BLBP expression is downstream of Ras-independent EGFR signaling. BLBP-blocking antibodies enabled process outgrowth from Nf1(-/-) TXF cells and restored interaction with axons, without affecting cell proliferation or migration. Following injury, BLBP expression was induced in normal sciatic nerves when nonmyelinating Schwann cells remodeled their processes. These data suggest that BLBP, stimulated by Ras-independent pathways, regulates Schwann cell-axon interactions in normal peripheral nerve and peripheral nerve tumors.
Mol Cell Biol 2003 Mar
PMID:Brain lipid binding protein in axon-Schwann cell interactions and peripheral nerve tumorigenesis. 1261 91


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