Inactivation of p53 by human T-cell lymphotropic virus type 1 tax requiresactivation of the NF-kappa B pathway and is dependent on p53 phosphorylation

p53 plays a key role in guarding cells against DNA damage and transformatio n. We previously demonstrated that the human T-cell lymphotropic virus type 1 (HTLV-1) Tax can inactivate p53 transactivation function in lymphocytes. The present study demonstrates that in T cells, Tax-induced p53 inactivati on is dependent upon NF-kappa B activation. Analysis of Tax mutants demonst rated that Tan inactivation of p53 function correlates with the ability of Tax to induce NF-kappa B but not p300 binding or CREB transactivation. The Tax-induced p53 inactivation can be overcome by overexpression of a dominan t I kappa B mutant. Tax-NF-kappa B-induced p53 inactivation is not due to p 300 squelching since overexpression of p300 does not recover p53 activity i n the presence of Tax. Further, using wild-type and p65 knockout mouse embr yo fibroblasts (MEFs), we demonstrate that the p65 subunit of NF-kappa B is critical for Tax-induced p53 inactivation. While Tax can inactivate endoge nous p53 function in wild-type MEFs, it fails to inactivate p53 function in p65 knockout MEFs. Importantly, Tax-induced p53 inactivation can be restor ed by expression of p65 in the knockout MEFs. Finally, we present evidence that phosphorylation of serines 15 and 392 correlates with inactivation of p53 by Tax in T cells. This study provides evidence that the divergent NF-k appa B proliferative and p53 cell cycle arrest pathways may be cross-regula ted at several levels, including posttranslational modification of p53.