The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance
The antitumor drug paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and eventually apoptosis. Upon assembly of the α /β-tubulin heterodimer, GTP becomes bound to both the α and β-tubulin monomers. During microtubule assembly, the GTP bound to β-tubulin is hyd...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2007-01-01
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| Series: | Cancer Informatics |
| Subjects: | |
| Online Access: | http://la-press.com/article.php?article_id=215 |
| _version_ | 1811333490712510464 |
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| author | J. Torin Huzil Ke Chen Lukasz Kurgan Jack A. Tuszynski |
| author_facet | J. Torin Huzil Ke Chen Lukasz Kurgan Jack A. Tuszynski |
| author_sort | J. Torin Huzil |
| collection | DOAJ |
| description | The antitumor drug paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and eventually apoptosis. Upon assembly of the α /β-tubulin heterodimer, GTP becomes bound to both the α and β-tubulin monomers. During microtubule assembly, the GTP bound to β-tubulin is hydrolyzed to GDP, eventually reaching steady-state equilibrium between free tubulin dimers and those polymerized into microtubules. Tubulin-binding drugs such as paclitaxel interact with β-tubulin, resulting in the disruption of this equilibrium. In spite of several crystal structures of tubulin, there is little biochemical insight into the mechanism by which anti-tubulin drugs target microtubules and alter their normal behavior. The mechanism of drug action is further complicated, as the description of altered β-tubulin isotype expression and/or mutations in tubulin genes may lead to drug resistance as has been described in the literature. Because of the relationship between β-tubulin isotype expression and mutations within β-tubulin, both leading to resistance, we examined the properties of altered residues within the taxane, colchicine and Vinca binding sites. The amount of data now available, allows us to investigate common patterns that lead to microtubule disruption and may provide a guide to the rational design of novel compounds that can inhibit microtubule dynamics for specific tubulin isotypes or, indeed resistant cell lines. Because of the vast amount of data published to date, we will only provide a broad overview of the mutational results and how these correlate with differences between tubulin isotypes. We also note that clinical studies describe a number of predictive factors for the response to anti-tubulin drugs and attempt to develop an understanding of the features within tubulin that may help explain how they may affect both microtubule assembly and stability. |
| first_indexed | 2024-04-13T16:53:38Z |
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| id | doaj.art-fffca29f85d94819adf91173c0ad13f7 |
| institution | Directory Open Access Journal |
| issn | 1176-9351 |
| language | English |
| last_indexed | 2024-04-13T16:53:38Z |
| publishDate | 2007-01-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cancer Informatics |
| spelling | doaj.art-fffca29f85d94819adf91173c0ad13f72022-12-22T02:38:53ZengSAGE PublishingCancer Informatics1176-93512007-01-013159181The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug ResistanceJ. Torin HuzilKe ChenLukasz KurganJack A. TuszynskiThe antitumor drug paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and eventually apoptosis. Upon assembly of the α /β-tubulin heterodimer, GTP becomes bound to both the α and β-tubulin monomers. During microtubule assembly, the GTP bound to β-tubulin is hydrolyzed to GDP, eventually reaching steady-state equilibrium between free tubulin dimers and those polymerized into microtubules. Tubulin-binding drugs such as paclitaxel interact with β-tubulin, resulting in the disruption of this equilibrium. In spite of several crystal structures of tubulin, there is little biochemical insight into the mechanism by which anti-tubulin drugs target microtubules and alter their normal behavior. The mechanism of drug action is further complicated, as the description of altered β-tubulin isotype expression and/or mutations in tubulin genes may lead to drug resistance as has been described in the literature. Because of the relationship between β-tubulin isotype expression and mutations within β-tubulin, both leading to resistance, we examined the properties of altered residues within the taxane, colchicine and Vinca binding sites. The amount of data now available, allows us to investigate common patterns that lead to microtubule disruption and may provide a guide to the rational design of novel compounds that can inhibit microtubule dynamics for specific tubulin isotypes or, indeed resistant cell lines. Because of the vast amount of data published to date, we will only provide a broad overview of the mutational results and how these correlate with differences between tubulin isotypes. We also note that clinical studies describe a number of predictive factors for the response to anti-tubulin drugs and attempt to develop an understanding of the features within tubulin that may help explain how they may affect both microtubule assembly and stability.http://la-press.com/article.php?article_id=215TubulinMicrotubuleIsotypePaclitaxelCancerResistanceMutant. |
| spellingShingle | J. Torin Huzil Ke Chen Lukasz Kurgan Jack A. Tuszynski The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance Cancer Informatics Tubulin Microtubule Isotype Paclitaxel Cancer Resistance Mutant. |
| title | The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance |
| title_full | The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance |
| title_fullStr | The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance |
| title_full_unstemmed | The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance |
| title_short | The Roles of β²-Tubulin Mutations and Isotype Expression in Acquired Drug Resistance |
| title_sort | roles of β² tubulin mutations and isotype expression in acquired drug resistance |
| topic | Tubulin Microtubule Isotype Paclitaxel Cancer Resistance Mutant. |
| url | http://la-press.com/article.php?article_id=215 |
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