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Inhibitory role of TGIF in the As2O3-regulated 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.

Journal of Biomedical Science
|January 23, 2008
PubMed

Insights

Arsenic trioxide (As(2)O(3)) treatment surprisingly represses p21 expression by recruiting TGIF/HDAC1 to Sp1 binding sites, inhibiting cell cycle arrest. This mechanism involves c-Jun phosphorylation by JNK, impacting solid tumor treatment strategies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Arsenic trioxide (As(2)O(3)) exhibits anti-cancer properties by inducing cell cycle arrest and apoptosis.
  • Previous studies identified opposing roles of ERK1/2 and JNK in regulating p21 expression via Sp1 in response to As(2)O(3).

Purpose of the Study:

  • To elucidate the functional cooperation between Sp1 and c-Jun in activating the p21 promoter.
  • To investigate the mechanism by which As(2)O(3) influences p21 expression through c-Jun phosphorylation and recruitment of co-factors.

Main Methods:

  • DNA affinity binding assays
  • Chromatin immunoprecipitation (ChIP)
  • Promoter activity assays
  • Western blotting for phosphorylated c-Jun

Main Results:

  • Sp1 and c-Jun were shown to functionally cooperate in activating the p21 promoter at specific Sp1 binding sites (-84/-64).
  • As(2)O(3)-induced phosphorylation of c-Jun at Ser63/73 led to the recruitment of TGIF/HDAC1 complex to the Sp1 binding sites.
  • This recruitment resulted in the suppression of p21 promoter activation, thereby inhibiting cell cycle arrest.

Conclusions:

  • TGIF/HDAC1 complex plays a critical role in As(2)O(3)-mediated repression of p21 expression.
  • The findings reveal a novel mechanism where As(2)O(3) inhibits cell cycle arrest by suppressing p21 expression through a JNK-c-Jun-TGIF/HDAC1 pathway.

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