Inhibition of p53 function, either through mutation or inhibition by viral transforming proteins, correlates strongly with the oncogenic potential of the cell. In the following report, we describe a unique mechanism of p53 inactivation that involves the interaction of p53 with the p65 subunit of NF-kB. The inactive p53 complex is induced in HTLV-I-transformed and ATL leukemic cells. This mechanism of p53 inhibition may occur in other human cancers. A small percentage of human T-lymphotropic virus type-I (HTLV-I)-transformed cells carry p53 mutations, and mutated p53 genes have been found in only one-fourth of ATL cases. We initially demonstrated that the wild-type p53 is stabilized and transcriptionally inactive in HTLV-transformed cells. The viral transcriptional activator Tax plays a role in both the stabilization and inactivation of p53. We further demonstrated that p53 is hyperphosphorylated at serines 15 and 392 in HTLV-I-transformed cells and that phosphorylation of p53 at these specific residues inactivates p53 by blocking its interaction with basal transcription factors. In T-lymphocytes, Tax-induced p53 inactivation is dependent upon NF-kB activation. Analysis of Tax mutants demonstrated that Tax inactivation of p53 function correlates with the ability of Tax to induce NF-kB. Further, the p65 subunit of NF-kB is critical and uniquely involved in the Tax-induced p53 inhibition pathway. Using chromatin immunoprecipitation assays we have determined that in HTLV-I-transformed cells, p53 and p65 form a complex on the inactive MDM2 promoter. Consistent with reduced transcription activity, TFIID binding is not observed. These studies provide evidence that the divergent NF-kB proliferative and p53 cell cycle arrest pathways may be cross-regulated at several levels which include post-translational modification of p53.AKT activation enhances resistance to apoptosis and induces cell survival signaling through multiple downstream pathways which include NF-kB. We recently reported that AKT is activated in HTLV-1-transformed cells and that Tax activation of AKT is linked to NF-eB 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-kB activation. Blocking AKT with the PI3K/AKT inhibitor LY294002 or AKT SiRNA prevented NF-kB 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 C81 cells abrogates in vitro IKKbeta 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 IKKbeta phosphorylation of IkBalpha in vitro suggesting selective activity of AKT on the IKKbeta complex. Finally, AKT pro-survival function in HTLV-1-transformed cells is linked to expression of the Bcl-xL gene. We suggest that AKT plays a role in activation of pro-survival pathways in HTLV-1-transformed cells, possibly through NF-kB activation and inhibition of p53 transcription activity. Checkpoint kinase 1 (Chk1) mediates diverse cellular responses to genotoxic stress, regulating the network of genome-surveillance pathways that coordinate cell cycle progression with DNA repair. Chk1 is essential for mammalian development and viability, and has been shown to be important for both S and G2 checkpoints. Last year we reported that the HTLV-1 Tax protein interacts directly with Chk1 and impairs its kinase activities in vitro and in vivo. The direct and physical interaction of Chk1 and Tax was observed in HTLV-1-infected T cells (C81, HuT 102 and MT-2) and transfected fibroblasts (293T) by coimmunoprecipitation and by in vitro GST pull-down assays.

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Division of Basic Sciences - NCI (NCI)
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Journo, Chloe; Filipe, Josina; About, Fredegonde et al. (2009) NRP/Optineurin Cooperates with TAX1BP1 to potentiate the activation of NF-kappaB by human T-lymphotropic virus type 1 tax protein. PLoS Pathog 5:e1000521
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Couto, Francesca M; Minn, Alexandra H; Pise-Masison, Cynthia A et al. (2007) Exenatide blocks JAK1-STAT1 in pancreatic beta cells. Metabolism 56:915-8
Wamunyokoli, Fred W; Bonome, Tomas; Lee, Ji-Young et al. (2006) Expression profiling of mucinous tumors of the ovary identifies genes of clinicopathologic importance. Clin Cancer Res 12:690-700
Park, H U; Jeong, S-J; Jeong, J-H et al. (2006) Human T-cell leukemia virus type 1 Tax attenuates gamma-irradiation-induced apoptosis through physical interaction with Chk2. Oncogene 25:438-47
Chevalier, S A; Meertens, L; Pise-Masison, C et al. (2006) The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax. Oncogene 25:4470-82
Kovanen, Panu E; Young, Lynn; Al-Shami, Amin et al. (2005) Global analysis of IL-2 target genes: identification of chromosomal clusters of expressed genes. Int Immunol 17:1009-21
Pise-Masison, Cynthia A; Brady, John N (2005) Setting the stage for transformation: HTLV-1 Tax inhibition of p53 function. Front Biosci 10:919-30
Jeong, Soo-Jin; Pise-Masison, Cynthia A; Radonovich, Michael F et al. (2005) A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 Inhibition in the absence of NF-kappaB transcriptional activity. J Biol Chem 280:10326-32
Pise-Masison, Cynthia A; Jeong, Soo-Jin; Brady, John N (2005) Human T cell leukemia virus type 1: the role of Tax in leukemogenesis. Arch Immunol Ther Exp (Warsz) 53:283-96

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