Abstract

We have found that the ansa macrolide maytansine, which is a competitive inhibitor of vinblastine for binding to tubulin, has different effects on the conformation of the tubulin molecule than does vinblasatine. Vinblastine quenches the intrinsic fluorescence of tubulin bi-phasically whereas maytansine does so mono-phasically. Maytansine enhances the alkylation of tubulin by (14C)iodoacetamide whereas vinblastine suppresses the alkylation of tubulin. We intend to do the following experiments. We want to examine the effect of maytansine on the circular dichroism spectrum of tubulin and to use electron microscopy to analyze maytansine-induced microtubule disassembly to see the nature of the intermediates. We will also analyze the direction of maytansine-induced disassembly using outer doublet seeds and pulse-labeled microtubules. We hope to determine inhibition constants for maytansine's blocking of microtubule assembly with tau and HMW 2 and to isolate and identify the peptide or peptides which contain the sulfhydryls whose alkylation maytansine enhances. We will also compare the effects of maytansine and its analogue ansamitocin P-3.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026376-06
Application #
3167281
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1979-07-01
Project End
1985-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Texas Health Science Center San Antonio
Department
Type
School of Medicine & Dentistry
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229

  Publications

Vent, Julia; Wyatt, Todd A; Smith, D David et al. (2005) Direct involvement of the isotype-specific C-terminus of beta tubulin in ciliary beating. J Cell Sci 118:4333-41
Dumontet, Charles; Isaac, Sylvie; Souquet, Pierre-Jean et al. (2005) Expression of class III beta tubulin in non-small cell lung cancer is correlated with resistance to taxane chemotherapy. Bull Cancer 92:E25-30
Gupta, Suvroma; Banerjee, Mithu; Poddar, Asim et al. (2005) Biphasic kinetics of the colchicine-tubulin interaction: role of amino acids surrounding the A ring of bound colchicine molecule. Biochemistry 44:10181-8
Yeh, I-Tien; Luduena, Richard F (2004) The betaII isotype of tubulin is present in the cell nuclei of a variety of cancers. Cell Motil Cytoskeleton 57:96-106
Walss-Bass, Consuelo; Kreisberg, Jeffrey I; Luduena, Richard F (2003) Effect of the antitumor drug vinblastine on nuclear betaII-tubulin in cultured rat kidney mesangial cells. Invest New Drugs 21:15-20
Jensen-Smith, Heather C; Eley, Jonquille; Steyger, Peter S et al. (2003) Cell type-specific reduction of beta tubulin isotypes synthesized in the developing gerbil organ of Corti. J Neurocytol 32:185-97
Perry, Brian; Jensen-Smith, Heather C; Luduena, Richard F et al. (2003) Selective expression of beta tubulin isotypes in gerbil vestibular sensory epithelia and neurons. J Assoc Res Otolaryngol 4:329-38
Jensen-Smith, Heather C; Luduena, Richard F; Hallworth, Richard (2003) Requirement for the betaI and betaIV tubulin isotypes in mammalian cilia. Cell Motil Cytoskeleton 55:213-20
Khan, Israr A; Luduena, Richard F (2003) Different effects of vinblastine on the polymerization of isotypically purified tubulins from bovine brain. Invest New Drugs 21:3-13
Xu, Keliang; Luduena, Richard F (2002) Characterization of nuclear betaII-tubulin in tumor cells: a possible novel target for taxol. Cell Motil Cytoskeleton 53:39-52

Showing the most recent 10 out of 67 publications