Activated AKT regulates NF-κB activation, p53 inhibition and cell survival in HTLV-1-transformed cells

被引:162
作者
Jeong, SJ [1 ]
Pise-Masison, CA [1 ]
Radonovich, MF [1 ]
Park, HU [1 ]
Brady, JN [1 ]
机构
[1] Natl Canc Inst, Virus Tumor Biol Sect, Cellular Oncol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA
关键词
HTLV-1; p53; NF-kappa B; AKT; p65; IKK;
D O I
10.1038/sj.onc.1208825
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
AKT activation enhances resistance to apoptosis and induces cell survival signaling through multiple downstream pathways. We now present evidence that AKT is activated in HTLV-1-transformed cells and that Tax activation of AKT is linked to NF-kappa B activation, p53 inhibition and cell survival. Overexpression of AKT wild type (WT), but not a kinase dead (KD) mutant, resulted in increased Tax-mediated NF-kappa B activation. Blocking AKT with the PI3K/AKT inhibitor LY294002 or AKT SiRNA prevented NF-kappa B activation and inhibition of p53. Treatment of C81 cells with LY294002 resulted in an increase in the p53-responsive gene MDM2, suggesting a role for AKT in the Tax-mediated regulation of p53 transcriptional activity. Further, we show that LY294002 treatment of C81cells abrogates in vitro IKK beta phosphorylation of p65 and causes a reduction of p65 Ser-536 phosphorylation in vivo, steps critical to p53 inhibition. Interestingly, blockage of AKT function did not affect IKKb phosphorylation of I kappa Ba in vitro suggesting selective activity of AKT on the IKKb complex. Finally, AKT prosurvival function in HTLV-1-transformed cells is linked to expression of Bcl-xL. We suggest that AKT plays a role in the activation of prosurvival pathways in HTLV-1-transformed cells, possibly through NF-kappa B activation and inhibition of p53 transcription activity.
引用
收藏
页码:6719 / 6728
页数:10
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