Human T-lymphotropic virus type I tax protein utilizes distinct pathways for p53 inhibition that are cell type-dependent

p53 plays a pivotal role in transmitting signals from many forms of genotox ic stress to genes and factors that control the cell cycle and apoptosis, W e have previously shown that the human T-lymphotropic virus type I Tax prot ein can inhibit p53 function. Recently we reported that Tax inhibits p53 fu nction in Jurkat cells and mouse embryo fibroblasts through a mechanism inv olving the nuclear factor kappaB pathway and correlates with phosphorylatio n on serines 15 and 392 of p53, However, several groups have also observed a mechanism that correlates with p300 binding of Tax. To address this contr oversy and to determine the mechanism by which Tax inhibits p53 function, w e examined the activation functions of Tax required for p53 inhibition. In HeLa and H1299 cells the cAMP-response element-binding protein/activating t ranscription factor activation function is essential, as demonstrated by th e Tax mutants M47 and K88k In addition, expression of exogenous p300 in H12 99 cells allows full recovery of p53 transactivation in the presence of Tax . Consistent with p300 being a limiting factor in H1299, Saos-2, and HeLa c ells, we found that the level of endogenous p300 is relatively low in these cells compared with Jurkat cells or the human T-lymphotropic virus type I- infected C81 and MT2 cells. Thus our data suggests that Tax utilizes distin ct mechanisms to inhibit p53 function that are cell type-dependent.