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J Biol Chem, Vol. 274, Issue 34, 23875-23882, August 20, 1999

A -Tubulin Leucine Cluster Involved in Microtubule Assembly and Paclitaxel Resistance^,

Manuel L. Gonzalez-Garay, Lily Chang, Kristie Blade, Donald R. Menick, and Fernando Cabral

From the Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77030 and the  Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425

Analysis of -tubulin alleles from nine paclitaxel-resistant Chinese hamster ovary cell lines revealed an unexpected cluster of mutations affecting Leu-215, Leu-217, and Leu-228. Six of the mutant alleles encode a His, Arg, or Phe substitution at Leu-215; another mutant allele has an Arg substitution at Leu-217; and the final two mutant alleles have substitutions of His or Phe at Leu-228. Using plasmids that allow tetracycline regulated expression, the L215H, L217R, and L228F mutations were introduced into a hemagglutinin antigen-tagged -tubulin cDNA and transfected into wild-type Chinese hamster ovary cells. In all three cases, low to moderate expression of the transfected mutant gene conferred paclitaxel resistance. Higher levels of expression caused disruption of microtubule assembly, cell cycle arrest at mitosis, and failure to proliferate. Consistent with reduced microtubule stability, cells expressing mutant hemagglutinin -tubulin had fewer acetylated microtubules than nonexpressing cells in the same population. These data, together with previous studies showing that the paclitaxel-resistant mutant cell lines have less stable microtubules, indicate that the leucine cluster represents an important structural motif for microtubule assembly.

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