p53 Activation: A Case against Sir

The p53 tumor suppressor is a critical transcription factor for controlling cell growth and apoptosis during times of cellular stress. In this issue of Cancer Cell, Lain et al. have used a p53-responsive reporter gene as the readout for screening small-molecule activators of p53 that could potentially reduce tumor growth. Using this approach, tenovin-6 was identified as a potent SIRT1 and SIRT2 inhibitor that indirectly activated p53 at single-digit micromolar concentrations. The identification of a specific sirtuin inhibitor has broad implications in understanding sirtuin-p53 signaling and the development of novel chemotherapeutics.