Inhibitory role of TGIF in the As2O3-regulated p21 WAF1/CIP1 expression.
Although arsenic is an infamous carcinogen, it has been effectively used to treat acute promyelocytic leukemia, and can induce cell cycle arrest or apoptosis in human solid tumors. Previously, we had demonstrated that opposing effects of ERK1/2 and JNK on p21 expression in response to arsenic trioxide (As(2)O(3)) are mediated through the Sp1 responsive elements of the p21 promoter in A431 cells. Presently, we demonstrate that Sp1, and c-Jun functionally cooperate to activate p21 promoter expression through Sp1 binding sites (-84/-64) by using DNA affinity binding, chromatin immunoprecipitation, and promoter assays. Surprisingly, As(2)O(3)-induced c-Jun(Ser63/73) phosphorylation can recruit TGIF/HDAC1 to the Sp1 binding sites and then suppress p21 promoter activation. We suggest that, after As(2)O(3 )treatment, the N-terminal domain of c-Jun phosphorylation by JNK recruits TGIF/HDAC1 to the Sp1 sites and then represses p21 expression. That is, TGIF is involved in As(2)O(3)-inhibited p21 expression, and then blocks the cell cycle arrest.
Liu
Zi-Miao
ZM
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Huang
Huei-Sheng
HS
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism
D001152:Arsenicals; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D010087:Oxides; D016329:Sp1 Transcription Factor; D006655:Histone Deacetylases; D000077237:Arsenic Trioxide