The gunmetal mouse reveals Rab geranylgeranyl transferase to be the major molecular target of phosphonocarboxylate analogues of bisphosphonates

Bone

Volumn 49, Issue 1, 2011, Pages 111-121

  Coxon, Fraser P ^a   Taylor, Adam ^a   Stewart, Charlotte A ^a,d   Baron, Rudi ^b,e   Seabra, Miguel C ^b   Ebetino, F Hal ^c   Rogers, Michael J ^a  

^a UNIVERSITY OF ABERDEEN   (United Kingdom)

^b NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^c Dundalk   (Ireland)

^d MEDPHARM LTD   (United Kingdom)

^e Cerenis Therapeutics   (France)

Author keywords

Bisphosphonate; Osteoclast; Phosphonocarboxylate; Rab geranylgeranyl transferase; Rab prenylation

Indexed keywords

2 (2 PYRIDYL) 1 ETHYLIDENE 1,1 PHOSPHONOCARBOXYLIC ACID; 2 HYDROXY 3 IMIDAZOL[1,2 A]PYRIDIN 3 YL 2 PHOSPHONOPROPIONIC ACID; 3 (1 METHYLPYRIDIN 1 IUM 3 YL) 2 PHOSPHONOPROPANOATE; 3 (3 PYRIDYL) 1 ETHYLIDENE 1,1 PHOSPHONOCARBOXYLIC ACID; 3 (3 PYRIDYL) 2 HYDROXY 2 PHOSPHONOCARBOXYLIC ACID; BISPHOSPHONIC ACID DERIVATIVE; FARNESYL TRANS TRANSFERASE; NE 10485; RAB GERANYLGERANYL TRANSFERASE; RISEDRONIC ACID; UNCLASSIFIED DRUG;

ANIMAL CELL; APOPTOSIS; ARTICLE; CELL VACUOLE; CELL VIABILITY; CELLULAR DISTRIBUTION; CONTROLLED STUDY; DRUG TARGETING; ENDOCYTOSIS; ENZYME INHIBITION; MACROPHAGE; MOUSE; NONHUMAN; OSTEOCLAST; PROTEIN PRENYLATION; RABBIT;

ALKYL AND ARYL TRANSFERASES; ANIMALS; APOPTOSIS; CELL COUNT; CELL LINE; CELL SURVIVAL; DIPHOSPHONATES; DITERPENES; ENDOCYTOSIS; ENZYME INHIBITORS; HETEROZYGOTE; MACROPHAGES; MICE; MICE, INBRED STRAINS; OSTEOBLASTS; OSTEOCLASTS; PROTEIN PRENYLATION; PROTEIN TRANSPORT; PYRIDINES; RABBITS; VACUOLES;

EID: 79958715188     PISSN: 87563282     EISSN: 87563282     Source Type: Journal    
DOI: 10.1016/j.bone.2011.03.686     Document Type: Article

References (45)

1. Ebetino F.H., Bayless A.V., Ambugey J.I., Ibbotsen K.J., Dansereau S., Ebrahiimpour A. Elucidation of a pharmacophore for the bisphosphonate mechanism of antiresorptive activity. Phosphorus Sulfur Silicon 1996, 109-110:217-220.
2. Coxon F.P., Helfrich M.H., Larijani B., Muzylak M., Dunford J.E., Marshall D., et al. Identification of a novel phosphonocarboxylate inhibitor of Rab geranylgeranyl transferase that specifically prevents Rab prenylation in osteoclasts and macrophages. J Biol Chem 2001, 276:48213-48222.
3. Coxon F.P., Ebetino F.H., Mules E.H., Seabra M.C., McKenna C.E., Rogers M.J. Phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase disrupt the prenylation and membrane localization of Rab proteins in osteoclasts in vitro and in vivo. Bone 2005, 37:349-358.
4. McKenna C.E., Kashemirov B.A., Blazewska K.M., Mallard-Favier I., Stewart C.A., Rojas J., et al. Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid. J Med Chem 2010, 53:3454-3464.
5. Zerial M., McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2001, 2:107-117.
6. Leung K.F., Baron R., Ali B.R., Magee A.I., Seabra M.C. Rab GTPases containing a CAAX motif are processed post-geranylgeranylation by proteolysis and methylation. J Biol Chem 2007, 282:1487-1497.
7. Baron R.A., Tavare R., Figueiredo A.C., Blazewska K.M., Kashemirov B.A., McKenna C.E., et al. Phosphonocarboxylates inhibit the second geranylgeranyl addition by Rab geranylgeranyl transferase. J Biol Chem 2009, 284:6861-6868.
8. Gomes A.Q., Ali B.R., Ramalho J.S., Godfrey R.F., Barral D.C., Hume A.N., et al. Membrane targeting of Rab GTPases is influenced by the prenylation motif. Mol Biol Cell 2003, 14:1882-1899.
9. Coxon F.P., Thompson K., Rogers M.J. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006, 6:307-312.
10. Rogers M.J., Crockett J.C., Coxon F.P., Monkkonen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone 2010, [Nov. 26, Electronic publication ahead of print].
11. Dunford J.E., Thompson K., Coxon F.P., Luckman S.P., Hahn F.M., Poulter C.D., et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001, 296:235-242.
12. Roelofs A.J., Hulley P.A., Meijer A., Ebetino F.H., Russell R.G., Shipman C.M. Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells. Int J Cancer 2006, 119:1254-1261.
13. Fournier P, Daubine F, Lundy MW, Rogers MJ, Ebetino FH, Clezardin P. Lowering bone mineral affinity of bisphosphonates as a therapeutic strategy to optimize skeletal tumor growth inhibition in vivo. Cancer Res 2008;68:8945-53.
14. Marma M.S., Xia Z.D., Stewart C., Coxon F., Dunford J.E., Baron R., et al. Synthesis and biological evaluation of alpha-halogenated bisphosphonate and phosphonocarboxylate analogues of risedronate. J Med Chem 2007, 50:5967-5975.
15. Benford H.L., Frith J.C., Auriola S., Monkkonen J., Rogers M.J. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol 1999, 56:131-140.
16. van Beek E., Lowik C., van der Pluijm G., Papapoulos S. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants In vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 1999, 14:722-729.
17. Fisher J.E., Rogers M.J., Halasy J.M., Luckman S.P., Hughes D.E., Masarachia P.J., et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999, 96:133-138.
18. Coxon F.P., Helfrich M.H., Van't Hof R., Sebti S., Ralston S.H., Hamilton A., et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000, 15:1467-1476.
19. Detter J.C., Zhang Q., Mules E.H., Novak E.K., Mishra V.S., Li W., et al. Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis. Proc Natl Acad Sci U S A 2000, 97:4144-4149.
20. Zhang Q., Zhen L., Li W., Novak E.K., Collinson L.M., Jang E.K., et al. Cell-specific abnormal prenylation of Rab proteins in platelets and melanocytes of the gunmetal mouse. Br J Haematol 2002, 117:414-423.
21. Taylor A, Mules EH, Seabra MC, Rogers MJ, Coxon FP. Impaired prenylation of Rab GTPases in the gunmetal mouse causes defects in bone cell function. doi:10.4161/sgtp.2.3.16488.
22. Armour K.E., Armour K.J., Gallagher M.E., Godecke A., Helfrich M.H., Reid D.M., et al. Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase. Endocrinology 2001, 142:760-766.
23. Stenbeck G., Horton M.A. Endocytic trafficking in actively resorbing osteoclasts. J Cell Sci 2004, 117:827-836.
24. Taylor A., Rogers M.J., Tosh D., Coxon F.P. A novel method for efficient generation of transfected human osteoclasts. Calcif Tissue Int 2007, 80:132-136.
25. Frith J.C., Monkkonen J., Auriola S., Monkkonen H., Rogers M.J. The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 2001, 44:2201-2210. (JID - 0370605).
26. Itzstein C, Coxon FP, Rogers MJ. The regulation of osteoclast function and bone resorption by small GTPases. manuscript accepted by Small GTPases.
27. Yu X.Z., Prekeris R., Gould G.W. Role of endosomal Rab GTPases in cytokinesis. Eur J Cell Biol 2007, 86:25-35.
28. Miserey-Lenkei S., Waharte F., Boulet A., Cuif M.H., Tenza D., El Marjou A., et al. Rab6-interacting protein 1 links Rab6 and Rab11 function. Traffic 2007, 8:1385-1403.
29. Miaczynska M., Christoforidis S., Giner A., Shevchenko A., Uttenweiler-Joseph S., Habermann B., et al. APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 2004, 116:445-456.
30. Barbieri M.A., Fernandez-Pol S., Hunker C., Horazdovsky B.H., Stahl P.D. Role of Rab5 in EGF receptor-mediated signal transduction. Eur J Cell Biol 2004, 83:305-314.
31. Lackner M.R., Kindt R.M., Carroll P.M., Brown K., Cancilla M.R., Chen C., et al. Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors. Cancer Cell 2005, 7:325-336.
32. Moosajee M., Tulloch M., Baron R.A., Gregory-Evans C.Y., Pereira-Leal J.B., Seabra M.C. Single choroideremia gene in nonmammalian vertebrates explains early embryonic lethality of the zebrafish model of choroideremia. Investig Ophthalmol Vis Sci 2009, 50:3009-3016.
33. Cheng K.W., Lahad J.P., Gray J.W., Mills G.B. Emerging role of RAB GTPases in cancer and human disease. Cancer Res 2005, 65:2516-2519.
34. Liu Y.J., Wang Q., Li W., Huang X.H., Zhen M.C., Huang S.H., et al. Rab23 is a potential biological target for treating hepatocellular carcinoma. World J Gastroenterol 2007, 13:1010-1017.
35. Bhuin T., Roy J.K. Rab11 is required for myoblast fusion in Drosophila. Cell Tissue Res 2009, 336:489-499.
36. Bergman M., Salman H., Djaldetti M., Alexandrova S., Punsky I., Bessler H. Ultrastructure of mouse striated muscle fibers following pravastatin administration. J Muscle Res Cell Motil 2003, 24:417-420.
37. Sakamoto K., Honda T., Yokoya S., Waguri S., Kimura J. Rab-small GTPases are involved in fluvastatin and pravastatin-induced vacuolation in rat skeletal myofibers. FASEB J 2007, 21:4087-4094.
38. Westwood F.R., Bigley A., Randall K., Marsden A.M., Scott R.C. Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity. Toxicol Pathol 2005, 33:246-257.
39. Rodman J.S., Wandinger-Ness A. Rab GTPases coordinate endocytosis-commentary. J Cell Sci 2000, 113:183-192.
40. Ghittoni R., Patrussi L., Pirozzi K., Pellegrini M., Lazzerini P.E., Capecchi P.L., et al. Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases. FASEB J 2005, 19:605-607.
41. Frith J.C., Rogers M.J. Antagonistic effects of different classes of bisphosphonates in osteoclasts and macrophages in vitro. J Bone Miner Res 2003, 18:204-212.
42. Seabra M.C., Mules E.H., Hume A.N. Rab GTPases, intracellular traffic and disease. Trends Mol Med 2002, 8:23-30.
43. Gordiyenko N.V., Fariss R.N., Zhi C., MacDonald I.M. Silencing of the CHM gene alters phagocytic and secretory pathways in the retinal pigment epithelium. Investig Ophthalmol Vis Sci 2010, 51:1143-1150.
44. Thompson K., Rogers M.J., Coxon F.P., Crockett J.C. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles following fluid-phase endocytosis. Mol Pharmacol 2006, 1624-1632.
45. Ali B.R., Nouvel I., Leung K.F., Hume A.N., Seabra M.C. A novel statin-mediated "prenylation block-and-release" assay provides insight into the membrane targeting mechanisms of small GTPases. Biochem Biophys Res Commun 2010, 397:34-41.