Enhanced sensitivity to hydrogen peroxide-induced apoptosis in Evi1 transformed Rat1 fibroblasts due to repression of carbonic anhydrase III

P. Roy, E. Reavey, M. Rayne, S. Roy, M. Abed El Baky, Y. Ishii, C. Bartholomew

研究成果: Contribution to journalArticle査読

25 被引用数 (Scopus)

抄録

EVI1 is a nuclear zinc finger protein essential to normal development, which participates in acute myeloid leukaemia progression and transforms Rat1 fibroblasts. In this study we show that enforced expression of Evi1 in Rat1 fibroblasts protects from paclitaxel-induced apoptosis, consistent with previously published studies. Surprisingly, however, these cells show increased sensitivity to hydrogen peroxide (H2O2)-induced apoptosis, demonstrated by elevated caspase 3 catalytic activity. This effect is caused by a reduction in carbonic anhydrase III (caIII) production. caIII transcripts are repressed by 92-97% by Evi1 expression, accompanied by a similar reduction in caIII protein. Reporter assays with the rat caIII gene promoter show repressed activity, demonstrating that Evi1 either directly or indirectly modulates transcription of this gene in Rat1 cells. Targeted knockdown of caIII alone, with Dicer-substrate short inhibitory RNAs, also increases the sensitivity of Rat1 fibroblasts to H2O2, which occurs in the absence of any other changes mediated by Evi1 expression. Enforced expression of caIII in Evi1-expressing Rat1 cells reverts the phenotype, restoring H2O 2 resistance. Together these data show that Evi1 represses transcription of caIII gene expression, leading to increased sensitivity to H2O2-induced apoptosis in Rat1 cells and might suggest the basis for the development of a novel therapeutic strategy for the treatment of leukaemias and solid tumours where EVI1 is overexpressed.

本文言語英語
ページ(範囲)441-452
ページ数12
ジャーナルFEBS Journal
277
2
DOI
出版ステータス出版済み - 1 2010

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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