Beyond the allosteric role of Fructose-2,6-bisphosphate: exploring its effects on gene expression and signal transduction.

Loading...
Thumbnail Image

Persistent link to this item

Statistics
View Statistics

Journal Title

Journal ISSN

Volume Title

Title

Beyond the allosteric role of Fructose-2,6-bisphosphate: exploring its effects on gene expression and signal transduction.

Published Date

2009-09

Publisher

Type

Thesis or Dissertation

Abstract

In diabetes, insulin is either not available or not effective in suppressing glucose output by the liver. Enhancing hepatic glucose flux through glycolysis by raising fructose-2,6-bisphosphate (F26BP) levels ameliorates the diabetic phenotype in type 1 and type 2 diabetic mouse models (WU et al. 2001b; WU et al. 2002). This is attributed to the well characterized allosteric effects F26BP has on glucose metabolism enzymes. Recent studies have determined that raising F26BP levels has an additional role in regulating gene expression and signal transduction proteins (WU et al. 2005; WU et al. 2004). In terms of glucose metabolism, raising F26BP levels stimulates glucokinase gene expression and inhibits glucose-6-phosphatase gene expression, thus, also favoring enhanced glycolysis. These effects are not limited to glucose metabolism, as raising F26BP levels in type 2 diabetic mice leads to decreased weight gain and adiposity as well as a decrease in lipogenic enzyme gene expression. To fully characterize this new role of raising F26BP levels on gene expression, a microarray together with iTRAQ proteomic analysis was carried out. Through functional analysis of the microarray biological pathways were identified that changed when F26BP levels were raised in type 2 diabetic mice. In this way a wider array of lipid and cholesterol metabolism genes was shown to be down-regulated. Additionally, several other novel effects of F26BP on gene expression were elucidated. Comparison of the microarray and proteomic datasets elucidated that 87% of the protein expression changes were concomitant with gene expression changes. It is our hypothesis that some of these gene and protein expression changes are mediated through F26BP effect on the insulin signaling pathway component, Akt. Raising F26BP levels in a streptozotocin-treated mouse model (type 1 diabetic) leads to increased Akt levels and phosphorylation at serine-473 (WU et al. 2004). Based on this, experiments were carried out to determine the mechanism by which F26BP activates Akt and interacts with the insulin signaling pathway. Raising F26BP in cultured cells enhances insulin's effect on Akt and this effect requires phosphatidylinositol-3 kinase to be active. However, different from what is observed in vivo, in cell culture F26BP alone is not able to affect Akt phosphorylation.

Description

University of Minnesota Ph.D. dissertation. September 2009. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Alex J. Lange. 1 computer file (PDF); viii, 125 pages.

Related to

Replaces

License

Collections

Series/Report Number

Funding information

Isbn identifier

Doi identifier

Previously Published Citation

Suggested citation

Khan, Salmaan Ahmed. (2009). Beyond the allosteric role of Fructose-2,6-bisphosphate: exploring its effects on gene expression and signal transduction.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/56720.

Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.