Insights into the molecular mechanism of p53 inhibition by HTLV type 1 Tax

The p53 protein plays a pivotal role in transmitting signals from many form s of genotoxic stress to genes and factors that control aspects of the cell cycle and death. Although mutated in approximately 60% of all human cancer s, only a minority of human T-lymphotropic virus type 1 (HTLV-1)-transforme d cells carry p53 mutations. Nevertheless, the p53 protein in HTLV-1-transf ormed cells is functionally inactive. We have previously demonstrated that the HTLV-1 Tax protein can inhibit p53 trans-activation function. Tax does not accomplish this by directly binding to p53, but rather by a unique mech anism that includes constitutive phosphorylation of p53 at Ser-15 and Ser-3 92. Analysis of Tax mutants in lymphocytes demonstrates that Tax-induced p5 3 inhibition correlates with the ability of Tax to activate NP-kappaB, but not p300 binding or CREB trans-activation. Consistent with these results, e xpression of the I-kappaB alpha (S32,36A) mutant that blocks NF-kappaB acti vation blocks Tax-mediated p53 inhibition. We further demonstrate the impor tance of Tax activation of NF-kappaB in p53 inhibition, using p65 knockout (KO) mouse embryo fibroblasts (MEFs). In the absence of p65 Tax could not i nhibit p53. Tax does activate IKK beta in the p65 KO MEFs, indicating that prenuclear events of NF-kappaB activation are not sufficient for Tax-mediat ed p53 inhibition, but rather NF-kappaB transcriptional activation is criti cal. Importantly, using phosphospecific antibodies, we demonstrate that pho sphorylation of p53 at Ser-15 and Ser-392 correlates with Tax-mediated inhi bition. In addition, mutation of p53 at Ser-15 and Ser-392 to alanines rend ers p53 resistant to Tax inhibition. This report reviews p53 inhibition by Tax and presents our current model.