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Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes

Huei-Sheng Huang1, Zi-Miao Liu, Duang-Yang Hong

  • 1Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. huanghs@mail.ncku.edu.tw

Toxicology and Applied Pharmacology
|January 16, 2010
PubMed

Insights

Arsenic trioxide (ATO) impacts cell death pathways. JNK1 inhibits ATO-induced p21 expression, a mechanism involving TGIF domains, and JNK inhibition enhances ATO-induced apoptosis in keratinocytes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Toxicology

Background:

  • Arsenic compounds exhibit dual roles as carcinogens and therapeutic agents.
  • Arsenic trioxide (ATO) induces cell death via mechanisms like apoptosis and cell cycle arrest.
  • Previous research linked ATO-induced p21 activation to A431 cell death, involving ERK1/2 and JNK1 signaling.

Purpose of the Study:

  • To investigate the inhibitory role of JNK1 in ATO-induced p21 expression.
  • To identify the specific domains of TGIF responsible for its interaction with JNK1 and its effect on p21 expression.
  • To evaluate the impact of JNK inhibition on ATO-induced apoptosis in keratinocytes.

Main Methods:

  • Over-expression of JNK1 in A431 cells.
  • GST pull-down assay and fluorescence resonance energy transfer (FRET) analysis.
  • Reporter assays to determine TGIF domain function.
  • Flow cytometry to assess apoptosis in HaCaT cells after treatment with JNK inhibitor SP600125 and ATO.

Main Results:

  • JNK1 overexpression inhibited p21 expression in A431 cells, associated with HDAC1 and TGIF.
  • The N-terminal domain (1-108) of TGIF was critical for binding with c-Jun.
  • The C-terminal domain (138-272) of TGIF was required to suppress ATO-induced p21 expression.
  • JNK inhibitor SP600125 enhanced ATO-induced apoptosis in HaCaT keratinocytes.

Conclusions:

  • JNK1 plays an inhibitory role in ATO-induced p21 expression through interactions involving TGIF and HDAC1.
  • Specific domains of TGIF mediate its inhibitory effects on p21 expression.
  • Inhibiting JNK1 potentiates ATO-induced apoptosis in keratinocytes, suggesting a therapeutic avenue.

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