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Molecular Cancer Therapeutics
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Article

Mutations in β-Tubulin Map to Domains Involved in Regulation of Microtubule Stability in Epothilone- resistant Cell Lines1

Lifeng He, Chia-Ping Huang Yang and Susan Band Horwitz
Lifeng He
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Chia-Ping Huang Yang
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Susan Band Horwitz
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DOI:  Published November 2001
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Abstract

The epothilones (Epos) are a group of natural products isolated from the myxobacterium, Sorangium cellulosum. They have a mechanism of action similar to that of Taxol, i.e., they stabilize microtubules and induce the formation of microtubule bundles in cells. Because they are simpler in structure than Taxol and preserve their activity in P-glycoprotein-expressing cells, they are being studied as potential antitumor drugs. In this work, a series of Epo-resistant A549 and HeLa cell lines have been selected and analyzed. Class I β-tubulin, the major isotype of β-tubulin in these Epo-resistant cell lines, has been sequenced in a search for mutations. In the Epo B-resistant A549 cells, there is a mutation at β292 from Gln to Glu, in the Epo A-resistant HeLa cell line there is a mutation at β173 from Pro to Ala, and in the Epo B-resistant HeLa cell line there is a heterozygous mutation at β422 from Tyr to a mixture of Tyr and Cys. These mutations are close to the M-loop, the nucleotide-binding site, and the microtubule-associated protein binding sites, respectively. It is likely that these mutations in β-tubulin provide cells with a mechanism of resistance to the Epos and taxanes. Among these resistant cell lines, A549.EpoB40 is hypersensitive to microtubule-destabilizing drugs, such as vinblastine and colchicine, and HeLa.EpoB1.8 is dependent on the Epos or taxanes for growth. Our studies provide evidence that the M-loop, the GTP binding site, and the microtubule-associated protein binding sites at the COOH terminus in β-tubulin are critical for the regulation of microtubule stability.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵1 Supported in part by USPHS Grants CA39821 and CA77263.

  • ↵2 To whom requests for reprints should be addressed, at Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2163; Fax: (718) 430-8959; shorwitz{at}aecom.yu.edu.

  • ↵3 The abbreviations used are: Epo, epothilone; RT-PCR, reverse transcription-PCR; Pgp, P-glycoprotein; MDR, multidrug resistance; MRP, multidrug resistance-associated protein; MAPs, microtubule-associated proteins; MTP, microtubule protein.

    • Accepted August 27, 2001.
    • Received June 11, 2001.
    • Revision received August 21, 2001.
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Molecular Cancer Therapeutics: 1 (1)
November 2001
Volume 1, Issue 1
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Mutations in β-Tubulin Map to Domains Involved in Regulation of Microtubule Stability in Epothilone- resistant Cell Lines1
Lifeng He, Chia-Ping Huang Yang and Susan Band Horwitz
Mol Cancer Ther November 1 2001 (1) (1) 3-10;

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Mutations in β-Tubulin Map to Domains Involved in Regulation of Microtubule Stability in Epothilone- resistant Cell Lines1
Lifeng He, Chia-Ping Huang Yang and Susan Band Horwitz
Mol Cancer Ther November 1 2001 (1) (1) 3-10;
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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