p53 Activation: a case against Sir

Abstract

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.

Figure 1. Tenovins Inhibit SIRT1 and SIRT2 function

The mammalian family of sirtuins consists of seven proteins with a variety of cellular functions. Tenovins specifically inhibit SIRT1 and SIRT2, two specific deacetylases for several downstream substrates including the tumor suppressor p53. Inhibition of SIRT1 and SIRT2 by tenovins at single-digit micromolar concentrations has a significant effect on the acetylation levels of their substrates.