Abstract 570: The integrated stress response kinase GCN2 regulates cell survival through p21/WAF1/CIP1 in response to nutrient deprivation.

Abstract

Abstract The tumor microenvironment is often characterized by deficiencies in nutrients, such as oxygen, glucose, and amino acids. Activation of the nutrient-sensing kinase GCN2, which constitutes one arm of the Integrated Stress Response (ISR), is one mechanism by which tumor cells cope with and adapt to nutrient stress. GCN2 phosphorylates the alpha subunit of the eukaryotic translation initiation factor eIF2, leading to global downregulation of translation to conserve amino acids and initiation of a transcriptional program through ATF4 to promote recovery from nutrient deprivation. Loss of GCN2 results in decreased tumor cell survival in vitro under conditions of amino acid deprivation and attenuated tumor growth in vivo in a variety of implanted animal tumor models. Our recent studies have shown that amino acid deprivation induces the cell cycle inhibitor p21 in a GCN2 dependent manner. GCN2 regulates p21 at the transcriptional and translational level. Induction of p21 mRNA occurs in both eIF2α S51A and p53 -/- cells, indicating that phosphorylation of eIF2α and expression of p53 are not required for GCN2 dependent transcriptional regulation. At the translational level, GCN2 phosphorylates eIF2α to prevent translational suppression of p21 transcript variants containing a 5’ uORF overlapping the true translation start site. Expression of p21 promotes cell survival during amino acid deprivation, suggesting a mechanism by which GCN2 regulates p21 in order to coordinate cell division with nutrient availability. In agreement with a pro-survival role, we observe p21 upregulation concomitant with ISR activation in a genetically engineered mouse of soft tissue sarcoma. These findings point to a novel mode of regulation of p21/WAF1/CIP1 by nutrient stress in the tumor microenvironment that contributes to tumor progression. Citation Format: Stacey L. Lehman, Jiangbin Ye, Constantinos Koumenis. The integrated stress response kinase GCN2 regulates cell survival through p21/WAF1/CIP1 in response to nutrient deprivation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 570. doi:10.1158/1538-7445.AM2013-570