Inhibition of p53 function, either through mutation or interaction with viral transforming proteins, correlates strongly with the oncogenic potential of the cell. Only 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. In previous studies, we demonstrated that wild-type p53 is stabilized and transcriptionally inactive in HTLV-transformed cells. Further, the viral transcriptional activator Tax plays a role in both the stabilization and inactivation of p53 through a mechanism involving the first 52 amino acids of p53. We first demonstrated that p53 is hyperphosphorylated at Serine 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. More recent studies demonstrate that 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, but not p300 binding or CREB transactivation. The Tax-induced p53 inactivation can be overcome by overexpression of a dominant IkB mutant. Tax/NF-kB-induced p53 inactivation is not due to p300 squelching since overexpression of p300 does not recover p53 activity in the presence of Tax. Further, we demonstrate that the p65 subunit of NF-kB is critical for Tax-induced p53 inactivation using wild-type and p65 knockout MEFs. While Tax can inactivate endogenous p53 function in wild-type MEFs, it fails to inactivate p53 function in p65 knockout MEFs. Importantly, Tax-induced p53 inactivation can be restored by expression of p65 in the knockout MEFs. Finally, we present evidence that demonstrates phosphorylation of Serines 15 and 392 correlates with inactivation of p53 by Tax in T-cells. 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. In non-lymphocyte cell types, the CREB/ATF-activation function of Tax is essential for inhibition of p53 activity. In these cells, Tax inhibits p53 function by squelching cellular CBP. Consistent with this hypothesis, expression of exogenous p300 in H1299 cells allows full recovery of p53 transactivation in the presence of Tax. Also consistent with p300 being a limiting factor in H1299, Saos-2, and HeLa cells, we find that the level of endogenous p300 is relatively low in these cells compared to Jurkat or the HTLV-I-infected C81 and MT2 cells. Thus our data suggests that Tax utilizes distinct mechanisms to inhibit p53 function which is cell-type dependent. We have also analyzed the functional activity of the p53 tumor suppressor in HTLV-2-transformed cells. Abundant levels of the p53 protein were detected in both HTLV-2A and -2B virus-infected cell lines. The p53 was functionally inactive, however, in both transient transfection assays using a p53 reporter plasmid and in induction of p53-responsive genes in response to gamma-irradiation. We further investigated HTLV-2A Tax and HTLV-2B Tax effects on p53 activity. Interestingly, although Tax-2A and -2B inactivate p53, the Tax-2A protein appears to inhibit p53 function less efficiently than either Tax-1 or Tax-2B. In transient co-transfection assays, Tax-1 and Tax-2B inactivated p53 by 80% while Tax-2A reduced p53 activity by 20%. In addition, Tax-2A does not increase the steady state level of cellular p53 as well as Tax-1 or -2B in the same assays. Co-transfection assays demonstrated that Tax-2A could efficiently transactivate CREB-responsive promoters to the same level as Tax-1 and Tax-2B, indicating the protein was functional. This report provides the first functional difference between the HTLV-2A and -2B subtypes. This comparison of the action of HTLV-1 and HTLV-2 Tax protein on p53 function will provide important insights into the mechanism of HTLV viral transformation. CD4+ T lymphocytes, the primary host for HTLV-I, undergo a series of changes which lead to T-cell activation, immortalization and transformation. To gain insight into the genetic difference between activated and HTLV-I-infected lymphocytes, we have performed Affymetrix GeneChip analysis of activated and HTLV-I-infected cells. Using the Hu6800 GeneChip, we identified approximately 763 genes whose expression is differentially regulated in at least three out of five HTLV-I cell lines. Classification of these genes into functional groups including cellular receptors, kinases, phosphatases, cytokines, signal proteins and transcription factors provides insight into genes and pathways that are differentially regulated during HTLV-I transformation.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
United States
Zip Code
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
Bonome, Tomas; Levine, Douglas A; Shih, Joanna et al. (2008) A gene signature predicting for survival in suboptimally debulked patients with ovarian cancer. Cancer Res 68:5478-86
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

Showing the most recent 10 out of 21 publications