Environmental stresses elicit programs of gene expression designed to remedy cellular injury, or alternatively induce apoptosis. An important contributor to stress adaptation is a family of protein kinases that phosphorylate eukaryotic initiation factor -2 (elF2). This proposal is centered on the elF2 kinase GCN2 (EIF2AK4) that is activated in response to amino acid starvation, UV irradiation and proteasome inhibition. GCN2 phosphorylation of elF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress. Accompanying this general protein synthesis control, elF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP transcriptional regulator ATF4. ATF4 also induces the expression of additional transcription factors, ATF3 and CHOP/GADD153, that assist in expression of stress responsive genes. Reduced translation by elF2 phosphorylation can also activate NF-nB by lowering the steady state-levels of the labile IDB regulatory protein. While many of the genes induced by elF2 phosphorylation are shared between different environmental stresses, GCN2 functions in conjunction with other stress pathways, such as those regulated by MAP kinases, to elicit gene expression programs that are tailored for the specific stress condition. Our hypothesis is that GCN2 recognizes different stresses and facilitates gene expression that is important for ameliorating cellular damage and treating and preventing disease. Consistent with this idea, mice deleted for GCN2 show sensitivity to nutritional deficiencies and aberrant eating behaviors. In this proposal, we will characterize the mechanisms regulating GCN2 and its role in cellular repair and detoxification in response to environmental stress. We propose four aims.
Aim 1 Characterize mechanisms activating GCN2 in response to diverse cellular stresses.
Aim 2 Characterize the mechanisms regulating ATF4 translation in response to elF2 phosphorylation.
Aim 3 Characterize the role of ATF3 in the elF2 kinase stress response.
Aim 4 Characterize the role of GCN2 in anti-cancer treatment. Addressing these major questions will increase our understanding of the process of cellular adaptation to environmental stress and its role in the treatment and prevention of human diseases such as diabetes, neurological dysfunctions, eating disorders, and cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Maas, Stefan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
Zip Code
Shao, Yu; Hernandez-Buquer, Selene; Childress, Paul et al. (2017) Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. Endocrinology 158:2722-2740
Young, Sara K; Shao, Yu; Bidwell, Joseph P et al. (2016) Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression. J Biol Chem 291:13780-8
Young, Sara K; Wek, Ronald C (2016) Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response. J Biol Chem 291:16927-35
Young, Sara K; Palam, Lakshmi Reddy; Wu, Cheng et al. (2016) Ribosome Elongation Stall Directs Gene-specific Translation in the Integrated Stress Response. J Biol Chem 291:6546-58
Kwon, Jason J; Willy, Jeffrey A; Quirin, Kayla A et al. (2016) Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential. Oncotarget 7:71635-71650
Young, Sara K; Baird, Thomas D; Wek, Ronald C (2016) Translation Regulation of the Glutamyl-prolyl-tRNA Synthetase Gene EPRS through Bypass of Upstream Open Reading Frames with Noncanonical Initiation Codons. J Biol Chem 291:10824-35
Wilson, Gabriel J; Lennox, Brittany A; She, Pengxiang et al. (2015) GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. Am J Physiol Endocrinol Metab 308:E283-93
Willy, Jeffrey A; Young, Sara K; Stevens, James L et al. (2015) CHOP links endoplasmic reticulum stress to NF-?B activation in the pathogenesis of nonalcoholic steatohepatitis. Mol Biol Cell 26:2190-204
Collier, Ann E; Wek, Ronald C; Spandau, Dan F (2015) Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response. J Invest Dermatol 135:2502-2511
Young, Sara K; Willy, Jeffrey A; Wu, Cheng et al. (2015) Ribosome Reinitiation Directs Gene-specific Translation and Regulates the Integrated Stress Response. J Biol Chem 290:28257-71

Showing the most recent 10 out of 53 publications