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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK088416-03
Application #
8383111
Study Section
Special Emphasis Panel (ZDK1-GRB-W (O1))
Program Officer
Castle, Arthur
Project Start
2010-12-01
Project End
2013-06-30
Budget Start
2012-12-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$32,474
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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; 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; 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
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