Abstract 3087: Regulation of p53 stability and activity by ribosomal protein S27a

Ribosomal proteins (RPs) play a critical role in tightly coordinating p53-dependent cell cycle checkpoint with ribosomal biogenesis. A number of RPs, including L5, L11, L23, L26, and S7, specifically bind to MDM2 and inhibit MDM2-mediated p53 ubiquitination and degradation, leading to p53 activation, in response to nucleolar stress triggered by the perturbation of ribosomal biogenesis. Here, we report S27a, a ribosomal protein from small subunit of ribosome and synthesized as an ubiquitin C-terminal extension protein (CEP80), as a novel MDM2 regulator. S27a interacts with MDM2 at the central acidic domain of MDM2 and suppresses MDM2-mediated p53 ubiquitination, leading to p53 activation and cell cycle arrest. Knockdown of endogenous S27a significantly attenuated p53 activation by treatment with a low dose (5 nM) of actinomycin D (Act D), which specifically inhibits RNA polymerase I activity leading to inhibition of rRNA synthesis and perturbation of ribosomal biogenesis, suggesting that S27a is a non-redundant MDM2 regulator in response to nucleolar stress. Interestingly, we also show that MDM2 ubiquitinates S27a, leading to protesomal degradation of S27a, in response to Act D treatment, suggesting that MDM2, in turn, controls S27a levels in response to nucleolar stress. Taken together, our results reveal that S27a regulates p53 activity in response to nucleolar stress via a novel and dynamic interplay between S27a and MDM2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3087. doi:10.1158/1538-7445.AM2011-3087