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Related Experiment Videos

Transcription factor c-Jun activation represses mdr-1 gene expression.

Ze-Hong Miao1, Jian Ding

  • 1Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.

Cancer Research
|August 9, 2003
PubMed
Summary

The study reveals that salvicine down-regulates multidrug resistance (MDR) gene expression by activating transcription factor c-Jun. This activation leads to reduced mdr-1 expression and increased apoptosis, suggesting c-Jun as a potential target for overcoming tumor MDR.

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Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancer is a significant challenge, often involving the mdr-1 gene.
  • Transcription factor c-Jun is hypothesized to negatively regulate human mdr-1 gene expression.
  • Salvicine, a novel topoisomerase II inhibitor, exhibits cytotoxicity towards MDR tumor cells and down-regulates mdr-1 expression.

Purpose of the Study:

  • To investigate the relationship between c-Jun activation and salvicine-induced down-regulation of mdr-1 expression in K562/A02 cells.
  • To elucidate the molecular mechanisms by which salvicine affects c-Jun and mdr-1 expression.
  • To explore the role of c-Jun in salvicine's cytotoxic and pro-apoptotic effects.

Main Methods:

  • Reverse-transcription PCR and Western blotting to analyze gene and protein expression.

Related Experiment Videos

  • Use of c-jun antisense oligodeoxynucleotides to inhibit c-Jun activity.
  • Analysis of c-Jun-N-terminal kinase (JNK) and c-Jun protein phosphorylation.
  • Electrophoretic mobility shift assay (EMSA) to assess transcription factor DNA binding activity.

    • Main Results:

    • Salvicine suppressed mdr-1 expression and promoted c-jun expression in K562/A02 cells.
    • c-Jun expression enhancement preceded mdr-1 reduction.
    • c-jun antisense oligodeoxynucleotides blocked salvicine's effects on c-Jun protein and mdr-1 expression, but not c-jun mRNA levels.
    • Salvicine increased JNK and c-Jun phosphorylation and enhanced activator protein 1 DNA binding activity.
    • c-jun antisense oligodeoxynucleotides inhibited salvicine-induced apoptosis and cytotoxicity.

    Conclusions:

    • Transcription factor c-Jun plays a key role in salvicine-mediated down-regulation of mdr-1 expression and induction of apoptosis in MDR K562/A02 cells.
    • A proposed pathway involves salvicine activating JNK and c-Jun, leading to self-amplified c-Jun expression, mdr-1 repression, and apoptosis.
    • c-Jun emerges as a potential therapeutic target for overcoming multidrug resistance in tumors.