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PO(2)-dependent differential regulation of multidrug resistance 1 gene expression by the c-Jun NH2-terminal kinase

Min Liu1, Dengwen Li, Ritu Aneja

  • 1Department of Genetics and Cell Biology, Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, Tianjin 300071, China.

The Journal of Biological Chemistry
|April 25, 2007
PubMed

Insights

The c-Jun NH(2)-terminal kinase (JNK) pathway represses multidrug resistance 1 (MDR1) gene expression in normoxia but activates it in hypoxia. This study elucidates the distinct molecular mechanisms governing JNK

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • Hypoxia significantly impacts gene expression, including multidrug resistance 1 (MDR1).
  • The c-Jun NH(2)-terminal kinase (JNK) pathway's role in hypoxia-induced MDR1 expression is not fully understood.
  • Conflicting evidence exists regarding JNK activity and MDR1 expression under normoxic conditions.

Purpose of the Study:

  • To investigate the dual role of the JNK pathway in regulating MDR1 gene expression under both normoxic and hypoxic conditions.
  • To elucidate the distinct molecular mechanisms by which JNK influences MDR1 expression in response to oxygen levels.

Main Methods:

  • Analysis of JNK pathway activation and its effect on MDR1 promoter activity.
  • Investigation of transcription factor binding (c-Jun, HIF1) to the MDR1 promoter.
  • Assessment of the involvement of histone deacetylase 5 and p300/CBP coactivator in JNK-mediated regulation.

Main Results:

  • JNK pathway represses MDR1 expression in normoxia via c-Jun binding to the activator protein 1 site, dependent on histone deacetylase 5.
  • JNK pathway activates MDR1 expression in hypoxia, independent of the activator protein 1 site.
  • Hypoxia-induced activation involves hypoxia-inducible factor 1 (HIF1) binding to the hypoxia response element, facilitated by HIF1alpha-c-Jun interaction and p300/CBP coactivator.

Conclusions:

  • The JNK pathway exhibits opposing effects on MDR1 expression depending on oxygen availability.
  • Distinct molecular mechanisms, involving different transcription factors and cofactors, mediate JNK's regulatory roles in normoxia and hypoxia.
  • Understanding these mechanisms is crucial for targeting MDR1 in diseases associated with hypoxia.

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