Metabolism of proteins is highly regulated in physiological and pathophysiological states such as diabetes, starvation, etc. Both within the whole organism and at the cellular level, proteins exist in a dynamic state, maintained by the relative balance of protein synthesis and degradation. The bulk of cellular protein degradation is via the ubiquitin proteolytic pathway which provides both selectivity and specificity. Herein, cellular proteins via their internal lysine residues are tagged with ubiquitin and degraded via the proteasome. This pathway is responsible for the enhanced proteolysis of skeletal muscle in insulin-dependent diabetes and for the turnover of many regulatory molecules of metabolism including IRS-1 and IRS-2, key components of insulin action. Recent evidence suggests this pathway may exist within the cell nucleus. Our overall hypothesis is that cellular protein degradation is regulated in part by its loci of activity within the cell. In addition, recent data suggest a new targeting pathway for proteolysis with tagging via a protein's N terminus.
The aims of the present proposal are thus (1) to analyze the motif, identify the components, and determine the physiological significance of N-terminus dependent ubiquitination of cellular proteins and (2) to define the subcellular sites and mechanisms responsible for protein degradation. These studies will be carried out using a variety of physiological, pharmacological, biochemical, molecular and cellular systems. Ultimately, the ability to modulate protein metabolism in physiological and pathophysiological states requires a detailed mechanistic understanding of the pathways of protein metabolism, the subject of the present proposal. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067620-04
Application #
7078660
Study Section
Metabolism Study Section (MET)
Program Officer
Somers, Scott D
Project Start
2003-06-01
Project End
2008-03-31
Budget Start
2006-06-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$328,690
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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