Transcriptional upregulation of the human MRP2 gene expression by serine/threonine protein kinase inhibitors

Łukasz Pułaski, J. Szemraj, T. Uchiumi, M. Kuwano, G. Bartosz

研究成果: Contribution to journalArticle査読

抄録

Transcriptional regulation by cellular signalling pathways of multidrug resistance proteins that pump anti-cancer drugs out of cells is one of key issues in the development of the multidrug resistance phenotype. In our study, we have used the reporter gene approach as well as determination of mRNA levels in two cancer cell lines of human origin, MCF-7 and A549, to study the regulation of multidrug resistance proteins 2 and 3 (MRP2 AND MRP3) by serine/threonine protein kinases. Since a prototypic PKC inducer, PMA, caused a marked upregulation of transcription from both human MRP2 and MRP3 promoters, a role for PKC isoforms in positive control of expression of these proteins could be postulated. Interestingly, broad-spectrum serine-threonine protein kinase inhibitors which also inhibit PKC, staurosporine and H-7, stimulated expression from the MRP2 promoter instead of inhibiting it. This effect was not seen for MRP3. MRP2 induction by staurosporine and H-7 was shown to have phenotypic consequences in whole cells, rendering them more resistant to etoposide and increasing their ability to export calcein through the plasma membrane. These results point to the involvement of serine/threonine protein kinases in negative regulation of the human MRP2 gene and to the necessity of testing novel anti-cancer drugs acting as protein kinase inhibitors with regard to their potential ability to induce multidrug resistance.

本文言語英語
ページ(範囲)113-119
ページ数7
ジャーナルJournal of Biological Regulators and Homeostatic Agents
19
3-4
出版ステータス出版済み - 7 1 2005

All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 免疫アレルギー学
  • 生理学
  • 免疫学
  • 腫瘍学
  • 内分泌学
  • 生理学(医学)
  • 癌研究

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