Abstract 4986: Nuclear PRAS40 regulates the cellular response to nucleolar stress

Abstract

Abstract The Proline-rich Akt Substrate of 40kDA (PRAS40) has recently been identified as a binding partner and inhibitor of the mammalian Target of Rapamycin Complex 1 (mTORC1), a growth factor- and nutrient-sensitive kinase whose activity promotes protein synthesis and cell growth. Despite its inhibitory effect on mTORC1, PRAS40 has been shown to promote cell survival in rodent models of spinal cord injury and tumorigenesis. Importantly, PRAS40 levels have also been found to correlate with poor prognosis in lung cancer patients, an effect not readily explained by mTORC1 inhibition. Here we demonstrate that in addition to its known cytoplasmic role in inhibiting mTORC1, PRAS40 also actively shuttles to the nucleus, where it congregates at the periphery of nucleoli and exists in a high-molecular weight complex void of mTORC1 components. Through immunoprecipitation and mass spectrometry analyses we have begun to identify members of this nuclear PRAS40 complex. Furthermore, we demonstrate that PRAS40 overexpression attenuates Actinomycin D-mediated induction of nucleolar stress markers. These findings may help to explain the apparent pro-tumorigenic effects of PRAS40 and identify the PRAS40 nuclear complex as a potential target for anti-cancer drug discovery. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4986. doi:1538-7445.AM2012-4986