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Related Experiment Videos

hMSH2 expression is driven by AP1-dependent regulation through phorbol-ester exposure.

Odile Humbert1, Ikbel Achour, Dominique Lautier

  • 1Institut de Pharmacologie et de Biologie Structurale, UMR 5089 CNRS, 205, Route de Narbonne, 31077, Toulouse Cedex, France. odile.humbert@ipbs.fr

Nucleic Acids Research
|September 23, 2003
PubMed
Summary

Protein kinase C (PKC) activation upregulates human MutS homolog 2 (hMSH2) expression via transcriptional control. This process involves the AP-1 transcription factor binding to the hMSH2 promoter, crucial for DNA repair and genomic stability.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Mammalian mismatch repair (MMR) is vital for genomic stability and cellular response to DNA damage.
  • Understanding the regulation of key MMR proteins like human MutS homolog 2 (hMSH2) is crucial for comprehending MMR dysfunction and its cellular consequences.
  • Previous studies indicated protein kinase C (PKC) activity regulates hMSH2 expression in myeloid leukemic cells.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling hMSH2 expression.
  • To investigate the role of protein kinase C (PKC) in modulating hMSH2 levels.
  • To identify transcription factors involved in the PKC-mediated regulation of hMSH2.

Main Methods:

  • Treatment of U937 cells with phorbol ester (TPA) to activate PKC.

Related Experiment Videos

  • Analysis of hMSH2 protein and mRNA levels.
  • Investigation of hMSH2 promoter activity using site-directed mutagenesis of AP-1 binding sites.
  • Utilizing a dominant-negative c-Jun factor to assess AP-1's role in vivo and in vitro.

    • Main Results:

    • PKC activation by TPA leads to increased hMSH2 protein levels, paralleled by elevated hMSH2 mRNA.
    • Results suggest transcriptional regulation of the hMSH2 gene upon TPA induction.
    • The AP-1 transcription factor is implicated in the transactivation of hMSH2.
    • Disruption of AP-1 binding sites or inhibition of c-Jun abolished TPA-induced hMSH2 overexpression.

    Conclusions:

    • PKC-mediated control of hMSH2 expression is, at least partially, dependent on AP-1 transactivation.
    • The findings highlight AP-1 as a key mediator in the transcriptional upregulation of hMSH2 by PKC.
    • This regulatory pathway is important for maintaining genomic stability through the MMR system.