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Disease relevance of Microtubules


Psychiatry related information on Microtubules

  • Formation of the TGN-early endosome network is microtubule dependent and may involve modification of membrane processes affected by microtubule-associated motor activity [6].
  • Our unprecedented finding that a small MAP-2 microtubule binding region fragment and MAP-2c can form structures resembling straight filaments or Pronase-treated paired helical filaments raises fundamental questions concerning the role of MAP-2 in the pathobiology of Alzheimer disease [7].
  • Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease [8].
  • The hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, which results in breakdown of the microtubule network and, consequently, a progressive retrograde degeneration of the affected neurons and, ultimately, dementia [9].
  • There was no significant (P>0.10) change in Pa(CO(2)) between WK and NREM sleep (and REM sleep when sufficient data were obtained) before or after implantation of microtubules and in studies after creating the neurotoxic lesions [10].

High impact information on Microtubules

  • GTPase activating protein (GAP), phosphatidylinositol 3-kinase (PI3-k) and microtubule associate protein kinase (MAPk2) [11].
  • The recent high-resolution analysis of the structure of tubulin and the microtubule has brought new insight to the study of microtubule function and regulation, as well as the mode of action of antimitotic drugs that disrupt normal microtubule behavior [12].
  • The regulation of the microtubule system includes transcription of different tubulin isotypes, folding of /¿-tubulin heterodimers, post-translation modification of tubulin, and nucleotide-based microtubule dynamics, as well as interaction with numerous microtubule-associated proteins that are themselves regulated [12].
  • We show that these proteins govern apical actin assembly and thus control the orientation, but not assembly, of ciliary microtubules [13].
  • Kinetochores that have not yet attached to microtubules catalyze the sequestration of Cdc20 by an inhibitor called Mad2 [14].

Chemical compound and disease context of Microtubules


Biological context of Microtubules

  • Here, we report that the AAA-ATPase Cdc48/p97 and its adapters Ufd1-Npl4, which have a well-established role in membrane functions, also regulate spindle disassembly by modulating microtubule dynamics and bundling at the end of mitosis [20].
  • In experiments using these sera, we show that there is neither complete nor partial segregation of beta-tubulin isotypes: both interphase cytoskeletal and mitotic spindle microtubules are mixed copolymers of all expressed beta-tubulin isotypes [21].
  • The mitotic checkpoint acts to inhibit entry into anaphase until all chromosomes have successfully attached to spindle microtubules [22].
  • Our data suggest that CLASP1 is required at kinetochores for attached microtubules to exhibit normal dynamic behavior [23].
  • TPX2 is required for Ran.GTP and chromatin-induced microtubule assembly in M phase extracts and mediates spontaneous microtubule assembly when present in excess over free importin alpha [24].

Anatomical context of Microtubules


Associations of Microtubules with chemical compounds

  • The loss of YPT1 function, studied in cells with the YPT1 gene on chromosome VI regulated by the galactose-inducible GAL10 promoter, led to arrested cells that were multibudded and exhibited a complete disorganization of microtubules and an apparent loss of nuclear integrity [30].
  • The protein was selectively extracted from microtubules using a combination of GTP and AMP-PNP [31].
  • Thus microtubules assembled in ATP and centrifuged through sucrose cushions to separate them from nucleotides continue to exhibit increased rates in the next assembly cycle in the absence of ATP [32].
  • The axoplasmic supernatant also supported movement of microtubules along a glass surface and movement of carboxylated latex beads along microtubules at 0.5 micron/sec [28].
  • Double fluorescent staining with CaM-RITC and fluorescein-labeled antibodies to tubulin and DNAase I revealed a mitochondrial distribution pattern similar to that of microtubule arrays but unrelated to actin cabling [33].

Gene context of Microtubules


Analytical, diagnostic and therapeutic context of Microtubules


  1. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Kulaga, H.M., Leitch, C.C., Eichers, E.R., Badano, J.L., Lesemann, A., Hoskins, B.E., Lupski, J.R., Beales, P.L., Reed, R.R., Katsanis, N. Nat. Genet. (2004) [Pubmed]
  2. Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells. Robertson, C.N., Roberson, K.M., Padilla, G.M., O'Brien, E.T., Cook, J.M., Kim, C.S., Fine, R.L. J. Natl. Cancer Inst. (1996) [Pubmed]
  3. Isolation of the microtubule-vesicle motor kinesin from rat liver: selective inhibition by cholestatic bile acids. Marks, D.L., LaRusso, N.F., McNiven, M.A. Gastroenterology (1995) [Pubmed]
  4. Dishevelled-1 regulates microtubule stability: a new function mediated by glycogen synthase kinase-3beta. Krylova, O., Messenger, M.J., Salinas, P.C. J. Cell Biol. (2000) [Pubmed]
  5. Characterization of the KLP68D kinesin-like protein in Drosophila: possible roles in axonal transport. Pesavento, P.A., Stewart, R.J., Goldstein, L.S. J. Cell Biol. (1994) [Pubmed]
  6. Brefeldin A causes a microtubule-mediated fusion of the trans-Golgi network and early endosomes. Wood, S.A., Park, J.E., Brown, W.J. Cell (1991) [Pubmed]
  7. In vitro polymerization of embryonic MAP-2c and fragments of the MAP-2 microtubule binding region into structures resembling paired helical filaments. DeTure, M.A., Zhang, E.Y., Bubb, M.R., Purich, D.L. J. Biol. Chem. (1996) [Pubmed]
  8. Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease. Hoffner, G., Kahlem, P., Djian, P. J. Cell. Sci. (2002) [Pubmed]
  9. Metabolic/signal transduction hypothesis of Alzheimer's disease and other tauopathies. Iqbal, K., Grundke-Iqbal, I. Acta Neuropathol. (2005) [Pubmed]
  10. Do neurotoxic lesions in rostral medullary nuclei induce/accentuate hypoventilation during NREM sleep? Martino, P.F., Forster, H.V., Feroah, T., Wenninger, J., Hodges, M., Pan, L.G. Respiratory physiology & neurobiology. (2003) [Pubmed]
  11. Signal transduction by the B cell antigen receptor and its coreceptors. Cambier, J.C., Pleiman, C.M., Clark, M.R. Annu. Rev. Immunol. (1994) [Pubmed]
  12. Structural insights into microtubule function. Nogales, E. Annu. Rev. Biochem. (2000) [Pubmed]
  13. Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Park, T.J., Haigo, S.L., Wallingford, J.B. Nat. Genet. (2006) [Pubmed]
  14. How do so few control so many? Nasmyth, K. Cell (2005) [Pubmed]
  15. Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action. Panda, D., Miller, H.P., Islam, K., Wilson, L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  16. Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin. Yoon, S.O., Shin, S., Mercurio, A.M. Cancer Res. (2005) [Pubmed]
  17. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Klauber, N., Parangi, S., Flynn, E., Hamel, E., D'Amato, R.J. Cancer Res. (1997) [Pubmed]
  18. Equilibrium binding studies of non-claret disjunctional protein (Ncd) reveal cooperative interactions between the motor domains. Foster, K.A., Correia, J.J., Gilbert, S.P. J. Biol. Chem. (1998) [Pubmed]
  19. Synthesis and accumulation of alphaB crystallin in C6 glioma cells is induced by agents that promote the disassembly of microtubules. Kato, K., Ito, H., Inaguma, Y., Okamoto, K., Saga, S. J. Biol. Chem. (1996) [Pubmed]
  20. The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis. Cao, K., Nakajima, R., Meyer, H.H., Zheng, Y. Cell (2003) [Pubmed]
  21. Free intermingling of mammalian beta-tubulin isotypes among functionally distinct microtubules. Lewis, S.A., Gu, W., Cowan, N.J. Cell (1987) [Pubmed]
  22. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Abrieu, A., Magnaghi-Jaulin, L., Kahana, J.A., Peter, M., Castro, A., Vigneron, S., Lorca, T., Cleveland, D.W., Labbé, J.C. Cell (2001) [Pubmed]
  23. Human CLASP1 is an outer kinetochore component that regulates spindle microtubule dynamics. Maiato, H., Fairley, E.A., Rieder, C.L., Swedlow, J.R., Sunkel, C.E., Earnshaw, W.C. Cell (2003) [Pubmed]
  24. Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity. Gruss, O.J., Carazo-Salas, R.E., Schatz, C.A., Guarguaglini, G., Kast, J., Wilm, M., Le Bot, N., Vernos, I., Karsenti, E., Mattaj, I.W. Cell (2001) [Pubmed]
  25. The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Shulman, J.M., Benton, R., St Johnston, D. Cell (2000) [Pubmed]
  26. Different axoplasmic proteins generate movement in opposite directions along microtubules in vitro. Vale, R.D., Schnapp, B.J., Mitchison, T., Steuer, E., Reese, T.S., Sheetz, M.P. Cell (1985) [Pubmed]
  27. In vivo analysis of Drosophila bicoid mRNA localization reveals a novel microtubule-dependent axis specification pathway. Cha, B.J., Koppetsch, B.S., Theurkauf, W.E. Cell (2001) [Pubmed]
  28. Organelle, bead, and microtubule translocations promoted by soluble factors from the squid giant axon. Vale, R.D., Schnapp, B.J., Reese, T.S., Sheetz, M.P. Cell (1985) [Pubmed]
  29. KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Nangaku, M., Sato-Yoshitake, R., Okada, Y., Noda, Y., Takemura, R., Yamazaki, H., Hirokawa, N. Cell (1994) [Pubmed]
  30. The ras-related YPT1 gene product in yeast: a GTP-binding protein that might be involved in microtubule organization. Schmitt, H.D., Wagner, P., Pfaff, E., Gallwitz, D. Cell (1986) [Pubmed]
  31. Identification of dynamin, a novel mechanochemical enzyme that mediates interactions between microtubules. Shpetner, H.S., Vallee, R.B. Cell (1989) [Pubmed]
  32. Regulation of the microtubule steady state in vitro by ATP. Margolis, R.L., Wilson, L. Cell (1979) [Pubmed]
  33. The identification of calmodulin-binding sites on mitochondria in cultured 3T3 cells. Pardue, R.L., Kaetzel, M.A., Hahn, S.H., Brinkley, B.R., Dedman, J.R. Cell (1981) [Pubmed]
  34. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E.M., Mandelkow, E. Cell (1997) [Pubmed]
  35. Rbl2p, a yeast protein that binds to beta-tubulin and participates in microtubule function in vivo. Archer, J.E., Vega, L.R., Solomon, F. Cell (1995) [Pubmed]
  36. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Kim, J.C., Badano, J.L., Sibold, S., Esmail, M.A., Hill, J., Hoskins, B.E., Leitch, C.C., Venner, K., Ansley, S.J., Ross, A.J., Leroux, M.R., Katsanis, N., Beales, P.L. Nat. Genet. (2004) [Pubmed]
  37. Interaction of reelin signaling and Lis1 in brain development. Assadi, A.H., Zhang, G., Beffert, U., McNeil, R.S., Renfro, A.L., Niu, S., Quattrocchi, C.C., Antalffy, B.A., Sheldon, M., Armstrong, D.D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G.D. Nat. Genet. (2003) [Pubmed]
  38. Radioimmunoassay for tubulin: a quantitative comparison of the tubulin content of different established tissue culture cells and tissues. Hiller, G., Weber, K. Cell (1978) [Pubmed]
  39. Pathway leading to correctly folded beta-tubulin. Tian, G., Huang, Y., Rommelaere, H., Vandekerckhove, J., Ampe, C., Cowan, N.J. Cell (1996) [Pubmed]
  40. Nucleotide-dependent angular change in kinesin motor domain bound to tubulin. Hirose, K., Lockhart, A., Cross, R.A., Amos, L.A. Nature (1995) [Pubmed]
  41. Decoration of the microtubule surface by one kinesin head per tubulin heterodimer. Harrison, B.C., Marchese-Ragona, S.P., Gilbert, S.P., Cheng, N., Steven, A.C., Johnson, K.A. Nature (1993) [Pubmed]
  42. Immunofluorescence localization of proteins of high molecular weight along intracellular microtubules. Sherline, P., Schiavone, K. Science (1977) [Pubmed]
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