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Arsenic trioxide phosphorylates c-Fos to transactivate p21(WAF1/CIP1) expression

Zi-Miao Liu1, Huei-Sheng Huang

  • 1Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Toxicology and Applied Pharmacology
|September 30, 2008
PubMed

Insights

High concentrations of arsenic trioxide (ATO) activate ERK1/2, boosting c-Fos and enhancing p21 gene expression by forming a complex with c-Jun and p300/CBP. This clarifies ATO

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Arsenic trioxide (ATO) has a dual role as a poison and a therapeutic agent, particularly in treating acute promyelocytic leukemia.
  • ATO's anti-tumor effects are concentration-dependent, necessitating a thorough understanding of its mechanisms of action for safe therapeutic use.
  • Previous research indicated opposing roles of ERK1/2 and JNK pathways in regulating p21(WAF1/CIP1) (p21) expression under ATO treatment in A431 cells.

Purpose of the Study:

  • To elucidate the concentration-dependent mechanisms of arsenic trioxide (ATO) in regulating gene expression.
  • To investigate the role of high-concentration ATO in sustaining ERK1/2 phosphorylation and its downstream effects on c-Fos and p21 gene expression.
  • To determine the specific phosphorylation sites on c-Fos crucial for its interaction with the p21 promoter.

Main Methods:

  • Utilized site-directed mutagenesis to identify critical phosphorylation sites on c-Fos.
  • Employed DNA affinity precipitation assays to assess the binding of c-Fos to the p21 promoter.
  • Conducted functional assays to evaluate the transactivation of p21 gene expression.

Main Results:

  • High concentrations of ATO sustain ERK1/2 phosphorylation, leading to increased c-Fos biosynthesis and stability.
  • Phosphorylation of specific C-terminal (Thr232, Thr325, Thr331, Ser374) and N-terminal (Ser70) sites on c-Fos is essential for its binding to the p21 promoter.
  • This interaction, along with dimerized dephosphorylated c-Jun, recruits p300/CBP to the Sp1 sites, activating p21 gene expression.

Conclusions:

  • High-concentration ATO activates the ERK1/2 pathway, enhancing c-Fos expression and subsequent p21 gene transactivation in A431 cells.
  • The study identifies key phosphorylation events in c-Fos that mediate its interaction with the p21 promoter.
  • These findings provide critical insights into the molecular mechanisms underlying ATO's therapeutic effects and highlight the importance of concentration-specific actions.

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