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Arsenic trioxide inhibits p21 expression through the functional domains of TGIF
Author(s) -
Huang HueiSheng,
Liu ZiMiao
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.585.4
Subject(s) - arsenic trioxide , acute promyelocytic leukemia , cell cycle checkpoint , chemistry , apoptosis , microbiology and biotechnology , cancer research , phosphorylation , biochemistry , cell cycle , biology , retinoic acid , gene
Arsenic trioxide (ATO) has been used in medicine for many years, and is especially important in the treatment of acute promyelocytic leukemia. Multiple mechanisms of action, including cell cycle arrest and apoptosis, have been proposed; however, the opposing effects of arsenic in cancer therapy remain controversial. We found that ATO‐induced activation of p21 WAF1/CIP1 (p21) led to A431 cell death through the antagonistic effects of the ERK1/2 and JNK1 signaling. Further, we noted that JNK induced phosphorylation of c‐Jun to recruit the TGIF/HDAC1 at the Sp1 sites, resulting in the suppression of p21 expression. Using the GST pull‐down assay and fluorescence resonance energy transfer analysis, we found the N‐terminal domain (amino acids 1‐108) of TGIF was critical to its binding with c‐Jun. In addition, using reporter assays, we observed that the C‐terminal domains (amino acids 138‐272) of TGIF, are essential to the suppression of ATO‐induced p21 expression. Thus, the domains of TGIF which carry out its inhibitory effects were identified.