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. ? ? ?
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