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)

Manumycin was reported to have inhibitory effect on farnesyltransferase by competing with the farnesyl pyrophosphate substrate. It exhibited different antiproliferative activity in human hepatocellular carcinoma HepG2 cells, primary cultured human cardiac muscle cells and human liver cells (CLC). HepG2 cells overexpressing ras gene were more sensitive to manumycin than the other cells. The difference might be related to Ras protein levels in these cell lines. Manumycin reduced the amount of functional ras localized at the cytoplasmic membrane, resulting in blocked C-raf-1 assocation with Ras. Manumycin inhibited ERK1/2 phosphorylation in HepG2 cells without reduced expression of ERK1/2 protein. The levels of protein MKP-1 were significantly up-regulated. Our study also demonstrated that manumycin inhibited p85/PI3K and Akt phosphorylation without reduced expression of p85/PI3K and Akt, and interfered with the association of p85/PI3K and Ras. These findings indicated that manumycin interfered with Ras membrane localization, shut down the downstream pathways of Ras and inhibited cell proliferation in HepG2 cells.
Int J Mol Med 2003 Jun
PMID:Manumycin inhibits cell proliferation and the Ras signal transduction pathway in human hepatocellular carcinoma cells. 1273 20

Farnesyltransferase inhibitors (FTIs) were developed to prevent Ras processing and thus to be effective agents for the treatment of cancers harbouring mutated ras. In the present study, HepG2 cells underwent internucleosomal DNA fragmentation after treatment with farnesyltransferase inhibitor manumycin (20 microM) for 12 h. Flow cytometric analysis showed that HepG2 cells were accumulated in the G2/M phase of the cell cycle and the number of apoptotic sub-G1 fraction of cells was increased after treatment with manumycin in a time-dependent manner. During the induction of apoptosis, expression of p53 and p21WAF1 was upregulated, phosphorylation of IkappaB-alpha was blocked, caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B were cleaved, and Bcl-2 and Bax protein expression remained unchanged. These results indicated that manumycin induced apoptosis in HepG2 cells. The induction of apoptosis by manumycin involved the upregulation of p53 and p21WAF1, the activation of caspases, and the inhibition of nuclear factor-kappaB (NF-kappaB) pathway. However, Bcl-2 and Bax are not associated with manumycin-mediated apoptosis.
Int J Mol Med 2003 Dec
PMID:Manumycin induces apoptosis in human hepatocellular carcinoma HepG2 cells. 1461 73

The effects of inhibitors of 2,3-oxidosqualene:lanosterol cyclase (cyclase) on cytochrome P450 expression were investigated in primary cultures of rat hepatocytes. Treatment of hepatocyte cultures for 24 h with either of the inhibitors [4'-(6-allyl-methyl-amino-hexyloxy)-2'-fluoro-phenyl]-(4-bromophenyl)-methanone fumarate (Ro 48-8071) or trans-N-(4-chlorobenzoyl)-N-methyl-(4-dimethylaminomethylphenyl)-cyclohexylamine (BIBX 79) selectively increased CYP3A mRNA and immunoreactive protein contents, with maximal accumulations occurring at 3 x 10(-5) M Ro 48-8071 and 10(-4) M BIBX 79. The abilities of Ro 48-8071, BIBX 79, and 3beta-(2-diethylaminoethoxy)androst-5-en-17-one.HCl (U18666A) to induce murine CYP3A were abolished in hepatocyte cultures prepared from pregnane X receptor (PXR)-null mice, and cotransfection of primary cultured rat hepatocytes with a dominant-negative PXR prevented cyclase inhibitor-inducible luciferase expression from a PXR-responsive reporter plasmid. Cyclase inhibitor-mediated CYP3A mRNA induction was eliminated when primary cultured rat hepatocytes were cotreated with any of the following agents that inhibit steps upstream of cyclase in the cholesterol biosynthetic pathway: squalestatin 1 (squalene synthase inhibitor), (E)N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzenemethanamine (NB-598, squalene monooxygenase inhibitor), or pravastatin (HMG-CoA reductase inhibitor). Ro 48-8071-inducible CYP3A mRNA expression was restored when pravastatin-treated cultures were incubated with medium containing mevalonate. The concentration-dependence of Ro 48-8071-mediated CYP3A mRNA induction corresponded to the cellular contents of metabolically labeled squalene 2,3-oxide and squalene 2,3:22,23-dioxide, but not 24(S),25-epoxycholesterol. These results indicate that cyclase inhibitors are capable of inducing CYP3A expression in primary cultured rat and mouse hepatocytes and that the effect is mediated as a consequence of cyclase blockade through the evoked accumulation of one or more squalene metabolites that activate the PXR.
Mol Pharmacol 2004 May
PMID:Induction of CYP3A by 2,3-oxidosqualene:lanosterol cyclase inhibitors is mediated by an endogenous squalene metabolite in primary cultured rat hepatocytes. 1510 59

The Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.
Mol Cell Biol 2004 Aug
PMID:Hematopoietic cell fate and the initiation of leukemic properties in primitive primary human cells are influenced by Ras activity and farnesyltransferase inhibition. 1528

Post-translational modifications are essential for the proper function of many proteins in the cell. The attachment of an isoprenoid lipid (a process termed prenylation) by protein farnesyltransferase (FTase) or geranylgeranyltransferase type I (GGTase-I) is essential for the function of many signal transduction proteins involved in growth, differentiation, and oncogenesis. FTase and GGTase-I (also called the CaaX prenyltransferases) recognize protein substrates with a C-terminal tetrapeptide recognition motif called the Ca1a2X box. These enzymes possess distinct but overlapping protein substrate specificity that is determined primarily by the sequence identity of the Ca1a2X motif. To determine how the identity of the Ca1a2X motif residues and sequence upstream of this motif affect substrate binding, we have solved crystal structures of FTase and GGTase-I complexed with a total of eight cognate and cross-reactive substrate peptides, including those derived from the C termini of the oncoproteins K-Ras4B, H-Ras and TC21. These structures suggest that all peptide substrates adopt a common binding mode in the FTase and GGTase-I active site. Unexpectedly, while the X residue of the Ca1a2X motif binds in the same location for all GGTase-I substrates, the X residue of FTase substrates can bind in one of two different sites. Together, these structures outline a series of rules that govern substrate peptide selectivity; these rules were utilized to classify known protein substrates of CaaX prenyltransferases and to generate a list of hypothetical substrates within the human genome.
J Mol Biol 2004 Oct 15
PMID:Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. 1545 70

HC11, a spontaneously immortalized murine mammary lineage maintains features of normal cells while HC11 H-ras transformed cells (HC11 ras) are tumorigenic. Ras transformation is associated with a lower Vitamin D receptor (VDR) mRNA content. Our goal was to investigate the mechanism underlying VDR mRNA differences between these cells. Although the VDR transcriptional rate measured by run-on assays did not differ between the cells, our data suggested a pos transcriptional mechanism involving higher VDR mRNA degradation in HC11 ras cells which was not due to mutations in its 3'-UTR region since sequences of mRNA obtained from HC11 and HC11 ras cells were identical. Treatment of HC11 ras cells with a farnesyltransferase inhibitor, which prevents ras activation, causing an enhancement of VDR mRNA levels, indicating an association between the ras signaling pathway and VDR mRNA instability. The present work suggests that the decreased mRNA levels in HC11 ras cells might in part be due to an early loss of stability.
J Steroid Biochem Mol Biol 2004 Sep
PMID:Ras activation is associated with vitamin D receptor mRNA instability in HC11 mammary cells. 1554 34

We have studied the mechanism of apoptosis elicited by the farnesyltransferase inhibitor (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662) in human myeloma cell lines. Low concentrations of BMS-214662 efficiently inhibited protein farnesylation but did not affect the activation of Akt. BMS-214662 treatment increased levels of the BH3-only protein PUMA; induced proapoptotic conformational changes of Bax and Bak; reduced Mcl-1 levels; caused mitochondrial transmembrane potential loss; induced cytochrome c release, caspase activation, apoptosis-inducing factor (AIF) nuclear translocation, and phosphatidylserine exposure; and allowed the development of apoptotic morphology. Western blot analysis of cell extracts revealed the activation of caspases 2, 3, 8, and 9 upon treatment with BMS-214662. The general caspase inhibitor Z-VAD-fmk significantly prevented BMS-214662-induced death in U266 and RPMI 8226 cells but not in NCI-H929 cells. A mixture of selective caspase inhibitors for caspases 9 [N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone (Z-LEHD-fmk)], 3 (Z-DEVD-fmk), and 6 (Z-VEID-fmk) approached the protective effect of Z-VAD upon cell death. However, Z-VAD-fmk did not prevent BMS-214662-induced Bax and Bak activation and decrease of Mcl-1 levels. According to its effect on cell death, Z-VAD-fmk inhibited nuclear translocation of AIF in RPMI 8226 and U266 but not in NCI-H929 cells. These results suggest that apoptosis triggered by BMS-214662 is initiated by a PUMA/Bax/Bak/Mcl-1-dependent mechanism. In some cell lines, Bax/Bak activation is not sufficient per se to induce mitochondrial failure and release of apoptogenic proteins, and so caspases need to be activated to facilitate apoptosis. After DeltaPsi(m) loss, execution of apoptosis was performed in all cases by a cytochrome c-enabled, caspase-9-triggered, caspase cascade and the nuclear action of AIF.
Mol Pharmacol 2005 Jun
PMID:Farnesyltransferase inhibitor BMS-214662 induces apoptosis in myeloma cells through PUMA up-regulation, Bax and Bak activation, and Mcl-1 elimination. 1573 11

There is an increasing rationale for effective combinations of endocrine therapy with novel drugs that target aberrant signal transduction pathways in estrogen receptor (ER) positive breast cancer. Prolonged endocrine therapy can be associated with an acquired increase in peptide growth factor signaling (EGFR, HER2), together with cross-talk activation of ER-dependent gene transcription and cell growth that leads to endocrine resistance. Current approaches to target these pathways include both the selective ER downregulator fulvestrant, and various signal transduction inhibitors (STIs). Fulvestrant can overcome resistance to tamoxifen (TAM-R) and long-term estrogen deprivation (LTED-R) in experimental models by reducing ER expression, and represents a current option for post-menopausal women with endocrine resistant ER+ve breast cancer. Emerging data suggest that fulvestrant's effect may be greater when combined with estrogen deprivation, and several phase III trials are assessing fulvestrant combined with aromatase inhibitors (AIs). Small molecule STIs such as tyrosine kinase inhibitors (TKIs), farnesyltransferase inhibitors (FTIs) and mTOR antagonists are also active in breast cancer. Pre-clinical data suggest that combined endocrine/STI therapy may result in greater growth inhibition than either therapy alone, and thus delay emergence of resistance. Several clinical trials are now examining STIs combined with AIs both in the tamoxifen-resistant and first-line advanced breast cancer setting, while pre-surgical studies are investigating the efficacy of combined endocrine/STI therapy utilising biological primary endpoints. This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area.
J Steroid Biochem Mol Biol 2005 May
PMID:Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance. 1599 63

Hutchinson-Gilford progeria syndrome (HGPS) is typically caused by mutations in codon 608 (G608G) of the LMNA gene, which activates a cryptic splice site resulting in the in-frame loss of 150 nucleotides from the lamin A message. The deleted region includes a protein cleavage site that normally removes 15 amino acids, including a CAAX box farnesylation site, from the lamin A protein. We investigated the processing of the C-terminus of the mutant protein, 'progerin', and found that it does not undergo cleavage and, indeed, remains farnesylated. The retention of the farnesyl group may have numerous consequences, as farnesyl groups increase lipophilicity and are involved in membrane association and in protein interactions, and is likely to be an important factor in the HGPS phenotype. To further investigate this, we studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities, as was also seen in HGPS fibroblasts, and resulted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, causing the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. These results implicate the abnormal farnesylation of progerin in the cellular phenotype in HGPS cells and suggest that FTIs may represent a therapeutic option for patients with HGPS.
Hum Mol Genet 2005 Oct 15
PMID:Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. 1612 33

Entamoeba histolytica is a unique protozoan parasite possessing both protein farnesyltransferase and geranylgeranyltrasferase I (GGT-I) for isoprenylation of small GTPases. In this study, we demonstrated unique enzymological properties of the amebic GGT-I (EhGGT-I), including substrate specificity and insensitivity to known mammalian inhibitors. Some of important residues of the catalytic beta subunit implicated in the specificity for GTPase acceptors and prenyl donors are substituted in EhGGT-I. Recombinant alpha and beta subunits of EhGGT-I, co-expressed in Escherichia coli, showed activity to transfer geranylgeranyl to both human wild-type (CVLS) and mutant (CVLL) H-Ras, while the mammalian GGT-I geranylgeranylated, but not farnesylated, only mutant H-Ras. All the representative amebic Ras and Rho/Rac small GTPases with phenylalanine, leucine, methionine, or alanine terminus were preferentially geranylgeranylated by EhGGT-I. This indicates that the acceptor specificity of the amebic GGT-I is remarkably broader than that of its mammalian counterpart. In contrast to EhFT, which farnesylates but not geranylgeranlylates solely EhRas4-CVVA, EhGGT-I also showed significant farnesyltransferase activity against Ras GTPase acceptors. EhGGT-I showed remarkable resistance to peptidomimetics known to inhibit mammalian GGT-I. Together with our previous observation that this parasite does not appear to depend on farnesylation for a majority of Ras and Rho/Rac, these data indicate that biological and biochemical advantages leading to the evolutional selection of this isoprenyl modification must exist uniquely in this parasitic protist. Finally, remarkable biochemical differences in binding to substrates and inhibitors between amebic and mammalian GGT-I highlight this enzyme as an attractive target for the development of new chemotherapeutics against amebiasis.
Mol Biochem Parasitol 2006 Feb
PMID:Characterization of protein geranylgeranyltransferase I from the enteric protist Entamoeba histolytica. 1630 Aug 41


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