p73 beta is associated with induction of apoptosis or cellular growth arrest, while NF-kappa B is closely related with promotion of resistance to programmed cell death. These biologically opposing activities between p73 beta and NF-kappa B propose a regulatory mechanism of critical turning on/off in cellular apoptotic or survival responses. In this study, we demonstrate that NF-kappa B-mediated transactivation is specifically downreaulated by p73 beta; conversely, p73 beta-transactivation is negatively regulated by functional expression of p65, NF-kappa B RelA subunit. The p73 beta transactivation domain (TA) and p65 NH-terminus are crucial for their negative regulation of p65- and p73 beta-mediated transactivation, respectively. Furthermore, p65- or p73 beta-interaction with p300 is reciprocally inhibited by their competitive binding to p300 in a restrict amount-dependent manner. Likewise, both p73 beta-activated apoptosis and p65-dependent increase of cell viability Lire reciprocally repressed by p65 and p73 beta, respectively. These results have important implications for p300-mediated regulatory mechanism between p73 beta- and p65-transactivation, by which both p73 beta and NF-kappa B could Mutually affect on their biological activities. Therefore, we propose that p300 is a transactivational regulator of competitively balanced cross-talk between p73 beta and p65.