Genomes and Genes
Summary: An enzyme that catalyzes the synthesis of geranylgeranyl diphosphate from trans, trans-farnesyl diphosphate and isopentenyl diphosphate.
- Capell B, Erdos M, Madigan J, Fiordalisi J, Varga R, Conneely K, et al. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2005;102:12879-84 pubmed..Last, treatment of both early- and late-passage human HGPS fibroblasts with FTIs resulted in significant reductions in nuclear blebbing. Our results suggest that treatment with FTIs represents a potential therapy for patients with HGPS. ..
- Harousseau J, Lancet J, Reiffers J, Lowenberg B, Thomas X, Huguet F, et al. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood. 2007;109:5151-6 pubmed
- Swanson K, Hohl R. Anti-cancer therapy: targeting the mevalonate pathway. Curr Cancer Drug Targets. 2006;6:15-37 pubmed..These clinical trials are reviewed along with evaluation of some of the potential problems with these agents in their clinical application. ..
- Capell B, Olive M, Erdos M, Cao K, Faddah D, Tavarez U, et al. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proc Natl Acad Sci U S A. 2008;105:15902-7 pubmed publisher..These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease. ..
- Schafer Hales K, Iaconelli J, Snyder J, Prussia A, Nettles J, El Naggar A, et al. Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function. Mol Cancer Ther. 2007;6:1317-28 pubmed..This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule. ..
- Varela I, Pereira S, Ugalde A, Navarro C, Suarez M, Cau P, et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med. 2008;14:767-72 pubmed publisher..Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities...
- Roberts P, Mitin N, Keller P, Chenette E, Madigan J, Currin R, et al. Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. J Biol Chem. 2008;283:25150-63 pubmed publisher..We conclude that a majority of Rho GTPases are targets for pharmacologic inhibitors of farnesyltransferase, Rce1, and Icmt. ..
- Wojciak Stothard B, Zhao L, Oliver E, Dubois O, Wu Y, Kardassis D, et al. Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia. Circ Res. 2012;110:1423-34 pubmed publisher..RhoB, a protein homologous to RhoA and activated by hypoxia, regulates neoplastic growth and vasoconstriction but its role in the regulation of pulmonary vascular function is not known...
- Hougland J, Lamphear C, Scott S, Gibbs R, Fierke C. Context-dependent substrate recognition by protein farnesyltransferase. Biochemistry. 2009;48:1691-701 pubmed publisher..A better understanding of the molecular recognition of substrates performed by FTase will aid in both designing new FTase inhibitors as therapeutic agents and characterizing proteins involved in prenylation-dependent cellular pathways. ..
- Rucktäschel R, Thoms S, Sidorovitch V, Halbach A, Pechlivanis M, Volkmer R, et al. Farnesylation of pex19p is required for its structural integrity and function in peroxisome biogenesis. J Biol Chem. 2009;284:20885-96 pubmed publisher..Thus, isoprenylation of Pex19p contributes to substrate membrane protein recognition for the topogenesis of PMPs, and our results highlight the importance of lipid modifications in protein-protein interactions. ..
- Lee R, Chang S, Trinh H, Tu Y, White A, Davies B, et al. Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes. Hum Mol Genet. 2010;19:1603-17 pubmed publisher..Like Fntb-deficient keratinocytes, Pggt1b-deficient keratinocytes did not proliferate in culture. Thus, both FTase and GGTase-I are required for the homeostasis of skin keratinocytes. ..
- Terry K, Casey P, Beese L. Conversion of protein farnesyltransferase to a geranylgeranyltransferase. Biochemistry. 2006;45:9746-55 pubmed
- Yang W, Yamada M, Tamura Y, Chang K, Mao J, Zou L, et al. Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance. J Pharmacol Exp Ther. 2011;339:832-41 pubmed publisher..These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis. ..
- Wasko B, Dudakovic A, Hohl R. Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate. J Pharmacol Exp Ther. 2011;337:540-6 pubmed publisher..Our study suggests that induction of autophagy in PC3 cells with these agents is probably dependent upon impairment of geranylgeranylation of GGTase II substrates. ..
- Shen N, Yu X, Pan F, Gao X, Xue B, Li C. An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism. J Biol Chem. 2011;286:14508-15 pubmed publisher..This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1. ..
- Robak T, Szmigielska Kapłon A, Pluta A, Grzybowska Izydorczyk O, Wolska A, Czemerska M, et al. Novel and emerging drugs for acute myeloid leukemia: pharmacology and therapeutic activity. Curr Med Chem. 2011;18:638-66 pubmed..This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future. ..
- Constantinescu D, Csoka A, Navara C, Schatten G. Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts. Exp Cell Res. 2010;316:2747-59 pubmed publisher..Further, our results show that similar to other HGPS phenotypes, FTI treatment has a beneficial effect on DSB repair. ..
- Pais J, Bowers K, Fierke C. Measurement of the alpha-secondary kinetic isotope effect for the reaction catalyzed by mammalian protein farnesyltransferase. J Am Chem Soc. 2006;128:15086-7 pubmed..To look at the chemical step, the kinetic isotope effect was measured as 1.154 +/- 0.006 for a peptide that is farnesylated slowly, and these data suggest that FTase proceeds via a concerted mechanism with dissociative character. ..
- Berndt N, Hamilton A, Sebti S. Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011;11:775-91 pubmed publisher..One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials. ..
- Han J, Oh S, Morgillo F, Myers J, Kim E, Hong W, et al. Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. J Natl Cancer Inst. 2005;97:1272-86 pubmed
- Young S, Fong L, Michaelis S. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis. J Lipid Res. 2005;46:2531-58 pubmed
- Price C, Al Quadan T, Santic M, Jones S, Abu Kwaik Y. Exploitation of conserved eukaryotic host cell farnesylation machinery by an F-box effector of Legionella pneumophila. J Exp Med. 2010;207:1713-26 pubmed publisher..In conclusion, this study shows novel localized recruitment of the host farnesylation machinery and its anchoring of an F-box effector to the LCV membrane, and this is essential for biological function in vitro and in vivo...
- Raponi M, Lancet J, Fan H, Dossey L, Lee G, Gojo I, et al. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood. 2008;111:2589-96 pubmed..Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib. ..
- Yang S, Qiao X, Fong L, Young S. Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation. Biochim Biophys Acta. 2008;1781:36-9 pubmed..Treatment with the FTI also improved body weight curves and reduced the number of spontaneous rib fractures. This study provides further evidence for a beneficial effect of an FTI in HGPS. ..
- Ivanov S, Charron G, Hang H, Roy C. Lipidation by the host prenyltransferase machinery facilitates membrane localization of Legionella pneumophila effector proteins. J Biol Chem. 2010;285:34686-98 pubmed publisher..Thus, these data indicate that Legionella utilize the host prenylation machinery to facilitate targeting of effector proteins to membrane-bound organelles during intracellular infection. ..
- Guo R, Cao R, Liang P, Ko T, Chang T, Hudock M, et al. Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007;104:10022-7 pubmed
- Basso A, Kirschmeier P, Bishop W. Lipid posttranslational modifications. Farnesyl transferase inhibitors. J Lipid Res. 2006;47:15-31 pubmed..This review will summarize the basic biology of FTIs, their antitumor activity in preclinical models, and the current status of clinical studies with these agents. ..
- Pan J, Yeung S. Recent advances in understanding the antineoplastic mechanisms of farnesyltransferase inhibitors. Cancer Res. 2005;65:9109-12 pubmed..Together, these findings may alter thinking about how to apply FTIs in the clinic. ..
- Toth J, Yang S, Qiao X, Beigneux A, Gelb M, Moulson C, et al. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc Natl Acad Sci U S A. 2005;102:12873-8 pubmed..0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes and suggest a potential strategy for treating these diseases. ..
- Ling Y, Li Z, Miranda K, Oldfield E, Moreno S. The farnesyl-diphosphate/geranylgeranyl-diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and a molecular target of bisphosphonates. J Biol Chem. 2007;282:30804-16 pubmed
- Fong L, Frost D, Meta M, Qiao X, Yang S, Coffinier C, et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006;311:1621-3 pubmed..The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria. ..
- Yang S, Meta M, Qiao X, Frost D, Bauch J, Coffinier C, et al. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J Clin Invest. 2006;116:2115-21 pubmed..These studies suggest that FTIs could be useful for treating humans with HGPS. ..
- Porcu G, Wilson C, Di Giandomenico D, Ragnini Wilson A. A yeast-based genomic strategy highlights the cell protein networks altered by FTase inhibitor peptidomimetics. Mol Cancer. 2010;9:197 pubmed publisher..Moreover, it stresses the importance of monitoring the MDR response in patients treated with FTIs. ..
- Yang S, Chang S, Ren S, Wang Y, Andres D, Spielmann H, et al. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin. Hum Mol Genet. 2011;20:436-44 pubmed publisher..These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation. ..
- Gordon L, Kleinman M, Miller D, Neuberg D, Giobbie Hurder A, Gerhard Herman M, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109:16666-71 pubmed publisher..Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status. ..
- Schaafsma D, Dueck G, Ghavami S, Kroeker A, Mutawe M, Hauff K, et al. The mevalonate cascade as a target to suppress extracellular matrix synthesis by human airway smooth muscle. Am J Respir Cell Mol Biol. 2011;44:394-403 pubmed publisher..These findings reveal mechanisms related to evidence for the positive impact of statins on pulmonary health. ..
- Wiemer A, Hohl R, Wiemer D. The intermediate enzymes of isoprenoid metabolism as anticancer targets. Anticancer Agents Med Chem. 2009;9:526-42 pubmed
- Martin L, Head J, Pancholi S, Salter J, Quinn E, Detre S, et al. The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther. 2007;6:2458-67 pubmed..Enhanced G1 arrest due to modulation of cell cycle regulatory proteins may be the underlying mechanism for the positive interaction between FTIs and tamoxifen. ..
- Marks R, Ho A, Robbel C, Kuna T, Berk S, Gajewski T. Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level. Blood. 2007;110:1982-8 pubmed..These results indicate that FTIs inhibit T-cell activation at the posttranscriptional level and also suggest that they may have potential as novel immunosuppressive agents. ..
- Saikia S, Parker E, Koulman A, Scott B. Four gene products are required for the fungal synthesis of the indole-diterpene, paspaline. FEBS Lett. 2006;580:1625-30 pubmed
- Marji J, O Donoghue S, McClintock D, Satagopam V, Schneider R, Ratner D, et al. Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition. PLoS ONE. 2010;5:e11132 pubmed publisher..Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging. ..
- Sousa S, Fernandes P, Ramos M. Farnesyltransferase inhibitors: a detailed chemical view on an elusive biological problem. Curr Med Chem. 2008;15:1478-92 pubmed..These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials. ..
- Niessner H, Beck D, Sinnberg T, Lasithiotakis K, Maczey E, Gogel J, et al. The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. J Invest Dermatol. 2011;131:468-79 pubmed publisher..Together, these findings suggest that the FTI lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells and may therefore represent an effective alternative for melanoma treatment. ..
- Glynn M, Glover T. Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet. 2005;14:2959-69 pubmed..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. ..
- Head J, Johnston S. New targets for therapy in breast cancer: farnesyltransferase inhibitors. Breast Cancer Res. 2004;6:262-8 pubmed
- Kurzrock R, Kantarjian H, Cortes J, Singhania N, Thomas D, Wilson E, et al. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood. 2003;102:4527-34 pubmed..09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS. ..
- Basso A, Mirza A, Liu G, Long B, Bishop W, Kirschmeier P. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem. 2005;280:31101-8 pubmed..These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336 enhancement of the anti-tumor response to other chemotherapeutics. ..
- Vallim M, Fernandes L, Alspaugh J. The RAM1 gene encoding a protein-farnesyltransferase beta-subunit homologue is essential in Cryptococcus neoformans. Microbiology. 2004;150:1925-35 pubmed..Protein farnesylation is required for the growth and cellular differentiation of C. neoformans and may provide novel targets for antifungal therapy. ..
- Cox A, Der C. Ras family signaling: therapeutic targeting. Cancer Biol Ther. 2002;1:599-606 pubmed..We review the current status of anti-Ras drug development, issues that have complicated their progression to the clinic, and possible future strategies for targeting Ras. ..
- Cox A. Farnesyltransferase inhibitors: potential role in the treatment of cancer. Drugs. 2001;61:723-32 pubmed..Studies to be completed over the next 2 or 3 years should define the appropriate patient populations, administration and scheduling necessary to optimise the use of these novel anticancer agents. ..
- Adjei A, Davis J, Erlichman C, Svingen P, Kaufmann S. Comparison of potential markers of farnesyltransferase inhibition. Clin Cancer Res. 2000;6:2318-25 pubmed..Our results indicate that unprocessed HDJ-2 and prelamin A should be suitable markers of FT inhibition in clinical samples. ..