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Inhibition of AP-1 transcription activator induces myc-dependent apoptosis in HL60 cells

 Seyeon Park  ;  Eun-Ryeong Hahm  ;  Chul-Hak Yang  ;  Dug-Keun Lee 
 JOURNAL OF CELLULAR BIOCHEMISTRY, Vol.91(5) : 973-986, 2004 
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jun/AP‐1 ; inhibitor ; HL60 cell ; apoptosis ; c‐myc
Transcriptional activation of AP-1 is intricately involved in cell proliferation and transformation. The natural product, nordihydroguaiaretic acid (NDGA) shows an inhibitory effect on the binding of jun/AP-1 protein to the AP-1 site in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated HL60 cells. The NDGA inhibits the auto-regulated de novo synthesis of c-jun mRNA in TPA-stimulated HL60 cells. Our data also determine that this compound induces proliferation inhibition and apoptosis in human leukemia HL60 cells. To obtain information on the functional role of the AP-1 inhibition by NDGA in apoptosis signaling, the effects of pharmacological inhibition of AP-1 binding on c-myc, p53, and bax protein level were determined. Our results indicate that treatment of cells with NDGA enhances c-myc, p53, and bax protein levels. To rule out the possibility that NDGA will induce apoptosis because of the effects on proteins other than AP-1, we investigated the effect of another AP-1 inhibitor, SP600125, which is specific to Jun-N-terminal kinase. SP600125 decreased not only the phosphorylation level of jun protein but also AP-1/DNA binding activity. Also, apoptosis was observed to be induced by SP600125, concomitant with the increase in c-myc, p53, and bax protein level. In addition, apoptosis induced by both AP-1 inhibitors was accompanied by the activation of a downstream apoptotic cascade such as caspase 9, caspase 3, and poly[ADP-ribose]polymerase (PARP). When the cells were treated with NDGA or SP600125 in the presence of antisense c-myc oligonucleotides, apoptosis was not observed and an increase of c-myc, p53, and bax proteins was not manifested. All these results show that the inhibition of the transcription factor AP-1 action is related with either the drug-induced apoptosis or the drug toxicity of the HL60 cells. The apoptosis induced by AP-1 inhibition may be dependent on c-myc protein levels suggesting that the c-myc protein induces apoptosis at a low level of AP-1 binding activity. Altogether, our findings suggest that the presence of the AP-1 signal acts as a survival factor that determines the outcome of myc-induced proliferation or apoptosis.
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5. Research Institutes (연구소) > Anesthesia and Pain Research Institute (마취통증의학연구소) > 1. Journal Papers
Yonsei Authors
Park, Se Yeon(박세연)
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