Abstract 5058: Phosphatase Nuclear Targeting Subunit (PNUTS) is phosphorylated by AKT kinase

Abstract

Abstract Phosphorylation of the tumor suppressor protein, Retinoblastoma (Rb) is associated with a highly proliferative state of the cell and cancer. Rb phosphorylation state is partly controlled by the activity of Protein Phosphatase 1 (PP1) which is regulated by Phosphatase Nuclear Targeting Subunit (PNUTS). It is likely that PNUTS plays a role in cell survival and/or apoptosis because siRNA mediated knockdown of PNUTS causes apoptosis in breast and colon cancer cells. This occurs through activation of PP1 phosphatase activity toward Rb which leads to Rb dephosphorylation which can trigger apoptosis. Here we show that PNUTS may be regulated by the PI3K-AKT pathway which has been shown to be involved in many cellular functions including proliferation, growth and survival. In addition, signaling in this pathway has been shown to be disrupted in several cancers. In response to a sub-lethal dose of UV radiation of HCT116 colon cancer cells, activation of the AKT kinase occurs, with phosphorylation of known AKT substrates GSK-3 and mdm2 observed. Phosphorylation of Ser473 of AKT further verifies AKT activation. Under these conditions PNUTS is phosphorylated by the AKT kinase. Inhibition of PNUTS phosphorylation occurs when cells are treated with the LY294002 PI3K-AKT pathway inhibitor. Thus PNUTS is a putative substrate of AKT, and may play an important role in the survival of cells in response to stress. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5058.