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
相关论文
共 44 条
[31]   Tumor surveillance via the ARF-p53 pathway [J].
Sherr, CJ .
GENES & DEVELOPMENT, 1998, 12 (19) :2984-2991
[32]  
Sizemore N, 1999, MOL CELL BIOL, V19, P4798
[33]   Distinct roles of the IκB kinase α and β subunits in liberating nuclear factor κB (NFκB) from IκB and in phosphorylating the p65 subunit of NF-κB [J].
Sizemore, N ;
Lerner, N ;
Dombrowski, N ;
Sakurai, H ;
Stark, GR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (06) :3863-3869
[34]   To die or not to die: how does p53 decide? [J].
Slee, EA ;
O'Connor, DJ ;
Lu, X .
ONCOGENE, 2004, 23 (16) :2809-2818
[35]   ISOLATION OF TRANSFORMING MURINE LEUKEMIA VIRUSES FROM MICE WITH A HIGH INCIDENCE OF SPONTANEOUS LYMPHOMA [J].
STAAL, SP ;
HARTLEY, JW ;
ROWE, WP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1977, 74 (07) :3065-3067
[36]   ONCOGENIC TRANSFORMATION BY THE TAX GENE OF HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I INVITRO [J].
TANAKA, A ;
TAKAHASHI, C ;
YAMAOKA, S ;
NOSAKA, T ;
MAKI, M ;
HATANAKA, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (03) :1071-1075
[37]   Putting the rap on Akt [J].
Thompson, JE ;
Thompson, CB .
JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (20) :4217-4226
[38]   PI3K/Akt signalling pathway and cancer [J].
Vara, JAF ;
Casado, E ;
de Castro, J ;
Cejas, P ;
Belda-Iniesta, C ;
González-Barón, M .
CANCER TREATMENT REVIEWS, 2004, 30 (02) :193-204
[39]  
VERNANT JC, 1988, LANCET, V1, P177
[40]   p53: Death star [J].
Vousden, KH .
CELL, 2000, 103 (05) :691-694