DBC1 and MSL2, two novel members of the p53 signaling network

The function of the tumor suppressor p53 as a sequence specific transcription factor controlling the expression of numerous target genes is critical for the regulation of cellular senescence, cell-cycle arrest and apoptosis. Lysine residues can be modified by a number of different post-translational modifications and in the case of p53, ubiquitination and acetylation have both been shown to have highly significant roles in its regulation. Identifying the regulatory mechanisms that control p53 ubiquitination and acetylation remains an important step in furthering the understanding of p53 regulation in vivo during normal homeostasis, as well as under conditions of stress induction. Here we identify DBC1 and MSL2 as two novel members of the p53 regulatory network.;Acetylation activates p53 activity and p53 deacetylation by Sirt1, a member of the evolutionary conserved Sirtuin protein family, negatively regulates and restricts p53 function and promotes cell survival. Sirt1-mediated deacetylase function is also implicated in p53-independent pathways and its effects on transcriptional factors such as FOXOs and PGC-1alpha directly modulate metabolic responses, validating the importance of the deacetylase activity of Sirt1. However, Sirt1 regulation in vivo is not well understood. Here, we show that DBC1 (Deleted in Breast Cancer 1) acts as an inhibitor of Sirt1 in human cells. DBC1-mediated Sirt1 repression leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNAi stimulates Sirt1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis, demonstrating that DBC1 promotes p53-mediated apoptosis through specific inhibition of Sirt1. In addition to DBC1, our study also identified Acetyl-CoA Carboxylase 1 as a novel interacting partner of Sirt1, yet the functional consequence of this interaction has yet to be determined.;In addition to targeting p53 for proteasomal degradation, ubiquitination also regulates p53 subcellular localization. Accumulating evidence suggests that cytoplasmic localization of p53 plays an active role in p53-mediated functions such as apoptosis and autophagy. Here we describe MSL2 (male specific lethal 2), a novel E3-ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3-ligases, MSL2-mediated p53 ubiquitination does not affect p53 stability. Moreover, the MSL2-mediated effect on p53 is Mdm2 independent. Thus, our study identifies an important ubiquitin ligase for modulating p53 subcellular localization.;Both DBC1 and MSL2 are previously unidentified members of the p53 regulatory network, having novel roles in the regulation of p53 by inhibiting the deacetylase Sirt1 or promoting p53 cytoplasmic localization respectively.