title: Expression of the SEPT9_i4 isoform confers resistance to microtubule-interacting drugs.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We have examined the effect of over-expression of SEPT9_i4 on the dynamics of microtubule polymer mass in cultured cells.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Chacko
authors.forename: Simon S
authors.initials: SS
authors.lastname: McDade
authors.forename: Severine
authors.initials: S
authors.lastname: Chanduloy
authors.forename: Stewart W
authors.initials: SW
authors.lastname: Church
authors.forename: Richard
authors.initials: R
authors.lastname: Kennedy
authors.forename: John
authors.initials: J
authors.lastname: Price
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hall
authors.forename: S E Hilary
authors.initials: SE
authors.lastname: Russell
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007053:Ice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D058112:Septins / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D007053:Ice; D020033:Protein Isoforms; D014747:Vinblastine; C474315:SEPTIN9 protein, human; D058112:Septins; D017239:Paclitaxel; D000077235:Vinorelbine