Expression of the SEPT9_i4 isoform confers resistance to microtubule-interacting drugs
| Autor: | Simon S. McDade, Richard D. Kennedy, J.H. Price, Alex Chacko, Stewart W. Church, Peter A. Hall, S. E. Hilary Russell, Severine Chanduloy |
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| Rok vydání: | 2011 |
| Předmět: |
Gene isoform
Cancer Research Paclitaxel macromolecular substances Septin Vinblastine Microtubules Polymerization GTP-binding protein regulators Microtubule Cell Line Tumor Humans Protein Isoforms Actin Messenger RNA biology Ice Vinorelbine General Medicine Flow Cytometry Cell biology Tubulin Oncology Drug Resistance Neoplasm biology.protein Molecular Medicine Cytokinesis Septins DNA Damage |
| Zdroj: | Cellular oncology (Dordrecht). 35(2) |
| ISSN: | 2211-3436 |
| Popis: | The evolutionarily conserved septin family of genes encode GTP binding proteins involved in a variety of cellular functions including cytokinesis, apoptosis, membrane dynamics and vesicle trafficking. Septin proteins can form hetero-oligomeric complexes and interact with other proteins including actin and tubulin. The human SEPT9 gene on chromosome 17q25.3 has a complex genomic architecture with 18 different transcripts that can encode 15 distinct polypeptides. Two distinct transcripts with unique 5' ends (SEPT9_v4 and SEPT9_v4*) encode the same protein. In tumours the ratio of these transcripts changes with elevated levels of SEPT9_v4* mRNA, a transcript that is translated with enhanced efficiency leading to increased SEPT9_i4 protein.We have examined the effect of over-expression of SEPT9_i4 on the dynamics of microtubule polymer mass in cultured cells.We show that the microtubule network in SEPT9_i4 over-expressing cells resists disruption by paclitaxel or cold incubation but also repolymerises tubulin more slowly after microtubule depolymerisation. Finally we show that SEPT9_i4 over-expressing cells have enhanced survival in the presence of clinically relevant microtubule acting drugs but not after treatment with DNAinteracting agents.Given that SEPT9 over-expression is seen in diverse tumours and in particular ovarian and breast cancer, such data indicate that SEPT9_v4 expression may be clinically relevant and contribute to some forms of drug resistance. |
| Databáze: | OpenAIRE |
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