Involvement of glycogen synthase kinase-3β in arsenic trioxide-induced p21 expression

Huei Sheng Huang, Zi Miao Liu, Ya Ling Cheng

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14 Citations (Scopus)


Arsenic trioxide (ATO) has been effectively used as a therapeutic agent to treat acute promyelocytic leukemia and solid tumors, via induction of cell cycle arrest or apoptosis. In our previous studies, we suggest that c-Jun might act as an adapter to regulate p21WAF1/CIP1 (p21) expression in response to ATO. Therefore, how to regulate the c-Jun to bind to the p21 promoter was further elucidated. It has been reported that glycogen synthase kinase-3β (GSK-3β) can phosphorylate the C-terminus (Ser243) of c-Jun to decrease its protein stability and DNA-binding ability and can also increase the degradation of p21 in resting condition or under ultraviolet irradiation. Therefore, we hypothesized that ATOinduced p21 expression might be through the inhibition of GSK-3β. Using the DNA affinity precipitation assay, ATO could dephosphorylate the C-terminus (Ser243) of c-Jun to enhance its binding to the p21 promoter and resultant p21 expression. ATO, as well as LiCl (GSK-3β inhibitor), could induce GSK-3βSer9 phosphorylation and p21 expression in a time- and dosedependent manner. Constitutively active GSK-3β, FlagGSKCA, and constitutively inactive GSK-3β, FlagGSKCI, were constructed to further confirm the involvement of GSK-3β in the ATO-induced p21 expression. However, the stability of p21 protein was increased by ATO, but not LiCl treatment using cycloheximide. Furthermore, ATO-induced GSK-3βSer9 phosphorylation was through the ERK pathway, but not the PI3K/Akt pathway. We suggest that, taken together, ATO-induced ERK phosphorylation could inhibit GSK-3β activity to dephosphorylate the C-terminus (Ser243) of c-Jun to increase p21 expression and resultant cell death.

Original languageEnglish
Pages (from-to)101-109
Number of pages9
JournalToxicological Sciences
Issue number1
Publication statusPublished - 2011 May

All Science Journal Classification (ASJC) codes

  • Toxicology


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