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 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 both the transcriptional and translational level. Upregulation of p21 results in cell cycle arrest and promotes survival under amino acid deprivation. In agreement with a pro-survival role, we observe p21 upregulation concomitant with ISR activation in a genetically engineered mouse model of soft tissue sarcoma. These findings point to a novel mechanism of p21 regulation in order to coordinate cell division with nutrient availability. Research supported by NCI R01CA094214. Citation Format: Stacey L. Lehman, Jiangbin Ye, Constantinos Koumenis. The Integrated Stress Response kinase GCN2 regulates cell proliferation and survival through combined transcriptional and translational control of p21 (Cip1/Waf1). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 487. doi:10.1158/1538-7445.AM2014-487
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