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

By May 1, 2018Stem Cells

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

Soo-Jin Jeong, Cynthia A Pise-Masison, Michael F Radonovich, Hyeon Ung Park
and John N Brady

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 ofAKT is linked to NF-jB activation, p53 inhibition and cell survival. Overexpression ofAKT wild type (WT), but not a kinase dead (KD) mutant, resulted in increased Tax-mediated NF-jB activation. Blocking AKT with the PI3K/AKT inhibitor LY294002 or AKT SiRNA prevented NF-jB activation and inhibition ofp53. Treatment ofC81 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 ofC81 cells abrogates in vitro IKKb phosphorylation ofp65 and causes a reduction ofp65 Ser-536 phosphorylation in vivo, steps critical to p53 inhibition. Interestingly, blockage of AKT function did not affect IKKb phosphorylation ofI jBa in vitro suggesting selective activity ofAK T on the IKKb complex. Finally, AKT prosurvival function in HTLV-1-transformed cells is linked to expression ofBcl-xL . We suggest that AKT plays a role in the activation ofprosur vival pathways in HTLV-1-transformed cells, possibly through NF-jB activation and inhibition ofp53 transcription activity.

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