The proposed project will test the hypothesis that hyperglycemia and diabetes, acting alone or in combination, cause increased flux of glucose through the hexosamine biosynthetic pathway which results in increased O-GlcNAcylation, decreased ubiquitination, and decreased proteosomal-mediated degradation of the 4E-BP1 in the liver. The upregulated expression of 4E-BP1, in turn, produces a shift from cap-dependent to cap-independent mRNA translation. Mammalian eIF4E binding proteins (4E- BPs) inhibit cap-dependent translation by binding to the cap-binding protein eIF4E and preventing its association with eIF4G. 5'-cap binding by eIF4E is typically thought of as the rate-limiting step in translation initiation, and as such the reversible phosphorylation of 4E-BP1 is one of the best characterized mechanisms for regulating mRNA binding. An unexplored mechanism that also likely contributes to the regulation of mRNA cap-binding is altered expression of one or more of the 4E-BPs. Upregulated expression of 4E-BP1 likely contributes to pathologies associated with maladapted metabolism, as a result of altered hepatic protein expression due to the shift from cap-dependent to cap-independent translation. In the proposed studies, we will use diabetic rats and HepG2 cells in culture to evaluate the mechanism through which hyperglycemia leads to upregulated expression of 4E-BP1 in the liver.

Public Health Relevance

The proposed project will explore the mechanism(s) through which hyperglycemia and/or the diabetic state induce upregulated expression of 4E-BP1 in the liver. Although the regulation of translation initiation by the reversible phosphorylation of 4E-BP1 has been extensively characterized, changes in the expression of the translational repressor are largely unexplored. Increased expression of the 4E-BP1 in the liver due to excess nutrients and the diabetic state likely contributes to pathologies associated with metabolic dysfunction and as a result is a critical area for exploration in regards to public health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-W (O1))
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Castle, Arthur
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Pennsylvania State University
Schools of Medicine
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Dennis, Michael D; Kimball, Scot R; Jefferson, Leonard S (2013) Mechanistic target of rapamycin complex 1 (mTORC1)-mediated phosphorylation is governed by competition between substrates for interaction with raptor. J Biol Chem 288:10-9
Kelleher, Andrew R; Kimball, Scot R; Dennis, Michael D et al. (2013) The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb. Am J Physiol Endocrinol Metab 304:E229-36
Dennis, Michael D; McGhee, Nora K; Jefferson, Leonard S et al. (2013) Regulated in DNA damage and development 1 (REDD1) promotes cell survival during serum deprivation by sustaining repression of signaling through the mechanistic target of rapamycin in complex 1 (mTORC1). Cell Signal 25:2709-16
Dennis, Michael D; Shenberger, Jeffrey S; Stanley, Bruce A et al. (2013) Hyperglycemia mediates a shift from cap-dependent to cap-independent translation via a 4E-BP1-dependent mechanism. Diabetes 62:2204-14
Dennis, Michael D; Jefferson, Leonard S; Kimball, Scot R (2012) Role of p70S6K1-mediated phosphorylation of eIF4B and PDCD4 proteins in the regulation of protein synthesis. J Biol Chem 287:42890-9
Dennis, Michael D; Schrufer, Tabitha L; Bronson, Sarah K et al. (2011) Hyperglycemia-induced O-GlcNAcylation and truncation of 4E-BP1 protein in liver of a mouse model of type 1 diabetes. J Biol Chem 286:34286-97