beta-Transducin repeat-containing protein (beta-TrCP), an E3 ligase, promotes the degradation of substrate proteins in response to various stimuli. Even though several beta-TrCP substrates have been identified to date, limited information of its upstream regulators is available. Here, we showed that SIRT1 suppresses beta-TrCP protein synthesis via post-translational degradation. SIRT1 depletion led to a significant increase in the beta-TrCP accumulation without affecting the mRNA level. Consistently, beta-TrCP protein accumulation induced by resveratrol was further enhanced upon SIRT1 depletion. Rescue of SIRT1 reversed the effect of resveratrol, leading to reduced beta-TrCP protein levels. Proteasomal inhibition led to recovery of beta-TrCP in cells with SIRT1 overexpression. Notably, the recovered beta-TrCP colocalized mostly with SIRT1. Thus, SIRT1 acts as a negative regulator of beta-TrCP synthesis via promoting protein degradation. (C) 2013 Elsevier Inc. All rights reserved.