Fuyuhiko Tamanoi, Ph.D.

Professor

310-2067318
1602 Molecular Sciences Bldg, 405 Hilgard Avenue

Research Interests

Signal Transduction:  The Ras superfamily G-proteins function as a molecular switch to regulate signaling pathways.  Currently, we are investigating a unique subfamily called Rheb G-protein.  Initially, Rheb was found in brain, but was later found to be ubiquitously expressed.  We have identified Rheb homologues in a number of organisms including fruit fly and yeasts, and defined unique features of this family of G-protein.  Genetic studies using fission yeast as well as Drosophila showed that Rheb plays critical roles in cell growth and regulation of cell cycle at the G1/S boundary.  In addition, yeast Rheb regulates amino acid uptake.  The effect of Rheb on cell growth is mediated by its role in the activation of the TOR/S6K signaling pathway. Rheb is downregulated by Tsc1/Tsc2 complex that acts as a GTPase activating protein (GAP) for Rheb.  Mutations in the Tsc1 or Tsc2 gene leads to genetic disorder called tuberous sclerosis that is associated with the appearance of benign tumors at multiple sites in the body.  Our current effort is aimed at defining proteins involved in the Rheb signaling pathway.

Articles related to this research area


Nanodelivery of anticancer drugs:  Another research interest of our lab is utilization of silica nanoparticles for controllable drug delivery system for cancer therapy.  One of the major problems in clinical use of anti-cancer drugs is that many of them are hydrophobic, which poses a critical obstacle for cancer therapy.  We have used mesoporous silica nanoparticles prepared in the presence of surfactants.  These nanoparticles have the diameter of approximately 130 nm and contain thousands of pores whose diameter is about 3 nm.  We incorporated different hydrophobic anticancer drugs, such as camptothecin (CPT) and taxol, into the pores of the mesoporous silica nanoparticles and delivered the drug to a variety of human cancer cells.  This caused cell death.  We are also exploring ways to use molecular valves to carry out controlled release of anti-cancer drugs with the mesoporous silica nanoparticles.  One approach is to use molecules that change conformation by light exposure to accomplishcontrolled delivery.  Targeting to cancer by attaching ligands specific to cancer cells is currently being investigatedin our lab.

Articles related to this research area


Protein lipidation and prenyltransferase inhibitors:  Protein prenylation is aposttranslational modification of proteins involving the addition of isoprenoids, intermediates in cholesterol biosynthesis.  Two types of modification, farnesylation and geranylgeranylation, occur with a variety of proteins.  Farnesylation is of particular interest, since many of these farnesylated proteins are involved in signal transduction.  Farnesylated proteins include Ras superfamily G-proteins as well as tyrosine phosphatases.  Farnesylation is catalyzed by protein farnesyltransferase which recognizes the CysAAX motif at the C-termini of substrate proteins and transfers a farnesyl group forming a thioether bond. This heterodimeric enzyme is conserved from yeast to human, and their genes have been identified in a variety of organisms.  Small molecule inhibitors of protein farnesyltransferase have been studied.  These inhibitors, called FTIs, block anchorage-independent growth of a wide variety of human cancer cells.  A number of animal studies have shown that FTIs inhibit the growth of tumors or even regress tumor growth and clinical trials of FTIs are ongoing.  Our study focuses on the mechanism how FTI affects human cancer cells.  More recently, we have also identified small molecule inhibitors of protein geranylgeranyltransferase I.  These compounds are identified from a novel library of allenoate derived compounds.  Our GGTIs inhibit proliferation of human cancer cell lines causing G1 cell cycle arrest.

Articles related to this research area

 

Publications

  1. Xue M, Zhong X, Shaposhnik Z, Qu Y, Tamanoi F, Duan X, Zink JI.pH-Operated Mechanized Porous Silicon Nanoparticles.J Am Chem Soc. 2011 Jun 15; 133(23):8798-801. Epub 2011 May 24.

  2. Ferris DP, Lu J, Gothard C, Yanes R, Thomas CR, Olsen JC, Stoddart JF, Tamanoi F, Zink JI. Synthesis of Biomolecule-Modified Mesoporous Silica Nanoparticles for Targeted Hydrophobic Drug Delivery to Cancer Cells. Small 2011, 19. doi: 10.1002/smll.201002300. [Epub ahead of print]

  3. Hardt M, Chantaravisoot N, Tamanoi F. Activating mutations of TOR (target of rapamycin).Genes Cells. 2011 Feb;16(2):141-51.

  4. Meng H, Xue M, Xia T, Zhao YL, Tamanoi F, Stoddart JF, Zink JI, Nel AE. Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. J Am Chem Soc 2010 Sep 15;132(36):12690-7.

  5. Jie Lu, Monty Liong, Zongxi Li, Jeffrey I. Zink, Fuyuhiko Tamanoi Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small. 2010

  6. Chantaravisoot, N. and Tamanoi F.TOR Signaling and Human Cancer.The Enzymes 2010; 28: 301-314.

  7. Parmar N. and Tamanoi F. Rheb G-Proteins and the Activation of mTORC1. The Enzymes 2010; 27: 39-53.

  8. Huaidong Jiang, Changyong Song, Chien-Chun Chen, Rui Xu, Kevin S. Raines, Benjamin P., Fahimian, Chien-Hung Lu, Ting-Kuo Lee, Akio Nakashima, Jun Urano, Tetsuya Ishikawa, Fuyuhiko Tamanoi and Jianwei Miao Quantitative 3D imaging of whole, unstained cells by using X-ray diffraction microscopy PNAS. 2010

  9. Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene. 2010 Mar 1.

  10. Nakashima A, Sato T, Tamanoi F. Fission yeast TORC1 regulates phosphorylation of ribosomal S6 proteins in response to nutrients and its activity is inhibited by rapamycin. J Cell Sci. 2010 Mar 1;123(Pt 5):777-86. Epub 2010 Feb 9.

  11. Sato T, Nakashima A, Tamanoi F. Tanpakushitsu Kakusan Koso. Rheb-mTOR signaling pathway involved in tumor formation. 2010 Jan;55(1):11-7. Review. Japanese.

  12. Klichko, Y., Liong, M., Choi, E., Angelos, S., Nel, A.E., Stoddart, J.F., Tamanoi, F. and Zink, J.I. Mesostructured silica for optical functionality, nanomachines, and drug delivery.  J.Am.Ceram.Soc.  2009; 92, S2-S10. PMCID: PM2761636

  13. Chan LN, Hart C, Guo L, Nyberg T, Davies BS, Fong LG, Young SG, Agnew BJ, Tamanoi F. A novel approach to tag and identify geranylgeranylated proteins. Electrophoresis. 2009 Oct;30(20):3598-606.

  14. Kugawa F, Suzuki T, Miyata M, Tomono K, Tamanoi F. Construction of a model cell line for the assay of MDR1 (multi drug resistance gene-1) substrates/inhibitors using HeLa cells.Pharmazie. 2009 May;64(5): 296-300.

  15. Lu L, Chan L, Fiji HD, Dahl R, Kwon O, Tamanoi F.  In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I.   Molecular Cancer Therapeutics  2009;8(5) May 2009. [Epub ahead of print]

  16. Sato T, Nakashima A, Guo L, Tamanoi F.  Specific activation of mTORC1 by RHEB G-protein in vitro involves enhanced recruitment of its substrate protein.   J Bio Chem.  2009 Mar 20.

  17. Zhou, J., Vos, C.C., Gjyrezi, A., Yoshida, M., Khuri, F.R., Tamanoi, F. and Giannakakou, P. The protein farnesyltransferase regulates HDAC6 activity in a microtube-dependent manner  J.Biol.Chem.  2009; [Epub ahead of print. PMC Journal] PMCID: PMC2665085

  18. Liong M, Lu J, Kovochich M, Xia T, Ruehm SG, Nel AE, Tamanoi F, Zink JI.  Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery.   ACS Nano.  2008 May 1.

  19. Davies, B.S., Yang, S.H., Farber, E., Lee, R., Buck, S.B., Andres, D.A., Spielmann, H., Agnew, B.J., Tamanoi, F., Fong, L.G. and Young, S.G.Increasing the length of progerin’s isoprenyl anchor does not worsen bone disease or survival in mice with Hutchinson-Gilford progeria syndrome  J.Lipid Res.  2009; 50, 126-134.

  20. Short, J.D., Houston, K.D., Dere, R., Cai, S.L., Kim, J., Johnson, C.L., Broaddus, R.R., Shen, J., Miyamoto, S., Tamanoi, F., Kwiatkowski, D., Mills, G.B. and Walker, C.L. AMP-activated protein kinase signalling results in cytoplasmic sequestration of p27.  Cancer Res.  2008; 68, 6496-6506. NIHMSID: NIHMS106495

  21. Sato T, Umetsu A, Tamanoi F.  Characterization of the Rheb-mTOR Signaling Pathway in Mammalian Cells: Constitutive Active Mutants of Rheb and mTOR.   Methods in Enzymol.  2008

  22. Lu J, Choi E, Zink JI, Tamanoi F.  Light-Activated Nanoimpeller-Controlled Drug Release in Cancer Cells.   Small.  2008 March 31.

  23. Ikeda, K., Morigasaki, S., Tatebe, H., Tamanoi, F. and Shiozaki, K. Fission yeast TOR complex 2 activates the AGC-family Gad8 kinase essential for stress resistance and cell cylcle control.   Cell Cycle.  2008; 7, 358-364. PMCID: PMC2274895

  24. Watanabe M, Fiji HD, Guo L, Chan L, Kinderman SS, Slamon DJ, Kwon O, Tamanoi F. Inhibitors of protein geranylgeranyltransferase-I and rab geranylgeranyltransferase identified from a library of allenoate derived compounds.   J Biol Chem.  2008 Jan 28.

  25. Aspuria PJ, Tamanoi F. The Tsc/Rheb signaling pathway controls basic amino acid uptake via the Cat1 permease in fission yeast.   Mol Genet Genomics.  2008 Jan 25.

  26. Aspuria PJ, Sato T, Tamanoi F.  The TSC/Rheb/TOR Signaling Pathway in Fission Yeast and Mammalian Cells: Temperature Sensitive and Constitutive Active Mutants of TOR.   Cell Cycle.  2007 May 21;6(14): 1692-5.

  27. Lu J, Liong M, Zink JI, Tamanoi F.  Mesoporous Silica Nanoparticles as a Delivery System for Hydrophobic Anticancer Drugs.   Small.  2007 Jun 13.

  28. Lu J, Liong M, Zink JI, Tamanoi F.  Mesoporous Silica Nanoparticles for Cancer Therapy: Energy-Dependent Cellular Uptake and Delivery of Paclitaxel to Cancer Cells.   NanoBiotechnology.  2008 Feb 20.

  29. Castellano S, Fiji HD, Kinderman SS, Watanabe M, Leon P, Tamanoi F, Kwon O. Small-molecule inhibitors of protein geranylgeranyltransferase type I.  J Am Chem Soc.  2007 Apr 17. No abstract available. PMID: 17439124

  30. Urano J, Sato T, Matsuo T, Otsubo Y, Yamamoto M, Tamanoi F.  Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells.   Proc Natl Acad Sci U S A.  2007 Feb; 104 (9):3514-3519.

  31. Patel PH, Tamanoi F.  Increased Rheb-TOR signaling enhances sensitivity of the whole organism to oxidative stress.   J Cell Sci.  2006 Oct 15;119(Pt 20):4285-92.

  32. Khazak V, Kato-Stankiewicz J, Tamanoi F, and Golemis E.A.  Yeast screens for inhibitors of Ras-Raf interaction and characterization of MCP inhibitors of Ras-Raf interaction.   Methods in Enzymology.  2005;407:612-29.

  33. Patel PH, Tamanoi F. Using Drosophila and yeast genetics to investigate a role for the Rheb GTPAse in cell growth. Methods in Enzymol.  2006; 407:612-29. PMID: 16757356.

  34. Urano J, Comiso MJ, Guo L, Aspuria PJ, Deniskin R, Tabancay AP Jr, Kato-Stankiewicz J, Tamanoi F.  Identification of novel single amino acid changes that result in hyperactivation of the unique GTPase, Rheb, in fission yeast.   Molecular Microbiology.  2005 Nov; 58(4):1074-86.

  35. Gau GL, Kato-Stankiewicz J, Jiang C, Miyamoto S, Guo L, Tamanoi F.  Farnesyltransferase inhibitors reverse altered growth and distribution of actin filaments in Tsc-deficient cells via inhibition of both rapamycin-sensitive and -insensitive pathways.   Mol Cancer Ther.  2005 Jun;4(6):918-26.

  36. Kho Y, Kim SC, Jiang C, Barma D, Kwon SW, Cheng J, Jaunbergs J, Weinbaum C, Tamanoi F, Falck J, Zhao Y.  A tagging-via-substrate technology for detection and proteomics of farnesylated proteins.   Proc Natl Acad Sci U S A.  2004 Aug 24;101(34):12479-84. Epub 2004 Aug 12.

  37. Aspuria PJ, Tamanoi F.  The Rheb family of GTP-binding proteins.   Cell Signal.  2004 Oct;16(10):1105-12.

  38. Uhlmann EJ, Li W, Scheidenhelm DK, Gau CL, Tamanoi F, Gutmann DH.  Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation.   Glia.  2004 Aug;47(2):180-8.

  39. Clarke S, Tamanoi F.  Fighting cancer by disrupting C-terminal methylation of signaling proteins.   J Clin Invest.  2004 Feb;113(4):513-5.

  40. Patel PH, Thapar N, Guo L, Martinez M, Maris J, Gau CL, Lengyel JA, Tamanoi F.  Drosophila Rheb GTPase is required for cell cycle progression and cell growth.  J Cell Sci.  2003 Sep 1;116(Pt 17):3601-10.

  41. Tabancay AP Jr, Gau CL, Machado IM, Uhlmann EJ, Gutmann DH, Guo L, Tamanoi F.  Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K.   J Biol Chem.  2003 Oct 10;278(41):39921-30. Epub 2003 Jul 17.

  42. Hamasaki A, Naka H, Tamanoi F, Umezawa K, Otsuka M.  A novel metal-chelating inhibitor of protein farnesyltransferase.   Bioorg Med Chem Lett.  2003 May 5;13(9):1523-6.

  43. Kato-Stankiewicz J, Hakimi I, Zhi G, Zhang J, Serebriiskii I, Guo L, Edamatsu H, Koide H, Menon S, Eckl R, Sakamuri S, Lu Y, Chen QZ, Agarwal S, Baumbach WR, Golemis EA, Tamanoi F, Khazak V.  Inhibitors of Ras/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells.   Proc Natl Acad Sci U S A.  2002 Oct 29;99(22):14398-403. Epub 2002 Oct 21.

  44. Tamanoi F, Kato-Stankiewicz J, Jiang C, Machado I, Thapar N.  Farnesylated proteins and cell cycle progression.   J Cell Biochem Suppl.  2001;Suppl 37:64-70. Review.

  45. Tamanoi F, Gau CL, Jiang C, Edamatsu H, Kato-Stankiewicz J. Protein farnesylation in mammalian cells: effects of farnesyltransferase inhibitors on cancer cells.  Cell Mol Life Sci.  2001 Oct;58(11):1636-49. Review.

  46. Yang W, Tabancay AP Jr, Urano J, Tamanoi F. Failure to farnesylate Rheb protein contributes to the enrichment of G0/G1 phase cells in the Schizosaccharomyces pombe farnesyltransferase mutant.  Mol Microbiol.  2001 Sep;41(6):1339-47.

  47. Finlin BS, Gau CL, Murphy GA, Shao H, Kimel T, Seitz RS, Chiu YF, Botstein D, Brown PO, Der CJ, Tamanoi F, Andres DA, Perou CM.  RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer.   J Biol Chem.  2001 Nov 9;276(45):42259-67. Epub 2001 Aug 31.

  48. Pervin S, Singh R, Gau CL, Edamatsu H, Tamanoi F, Chaudhuri G.  Potentiation of nitric oxide-induced apoptosis of MDA-MB-468 cells by farnesyltransferase inhibitor: implications in breast cancer.  Cancer Res. 2001 Jun 15;61(12):4701-6.

  49. Urano J, Ellis C, Clark GJ, Tamanoi F. Characterization of Rheb functions using yeast and mammalian systems.  Methods Enzymol.  2001;333:217-31. No abstract available.

  50. Guo W, Tamanoi F, Novick P.  Spatial regulation of the exocyst complex by Rho1 GTPase.  Nat Cell Biol. 2001 Apr;3(4):353-60.

  51. Urano J, Tabancay AP, Yang W, Tamanoi F.  The Saccharomyces cerevisiae Rheb G-protein is involved in regulating canavanine resistance and arginine uptake.   J Biol Chem. 2000 Apr 14;275(15):11198-206.

  52. Edamatsu H, Gau CL, Nemoto T, Guo L, Tamanoi F.  Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines.   Oncogene.  2000 Jun 22;19(27):3059-68.

  53. Yang W, Urano J, Tamanoi F.  Protein farnesylation is critical for maintaining normal cell morphology and canavanine resistance in Schizosaccharomyces pombe.   J Biol Chem.  2000 Jan 7;275(1):429-38.