O-GlcNAc is the covalent modification of proteins at serine/threonine amino acids by the sugar moiety Nacetylglucosamine. The O-GlcNAc modification is not elongated to more complex oligosaccharide structures and is found only on nuclear and cytoplasmic proteins. The modification is highly dynamic and responds to signals of the extracellular environment such hormones, stress, and nutrients. Previously, I demonstrated that 0-GlcNAc is critical for the proper progression of the cell cycle in eukaryotic cells;gain of function of either 0-GlcNAc transferase (OGT), the enzyme which adds the modification, or 0-GlcNAcase (OGA), the enzyme which removes the modification, causes mitotic exit delays. Furthermore, OGT and OGA can be found in a signaling complex with mitotic kinases such as Aurora Kinase B. The goal of this proposal is to investigate the interactions of OGT with mitotic structures such as the spindle and with mitotic proteins. We hypothesize that OGT forms complexes with various proteins during M phase progression that then targets OGT the spindle and midbody. I plan to use multiple techniques such as using FRAP (Fluorescent Recovery after Photo-bleaching) on GFP-OGT to measure the kinetics of OGT at spindle/midbody, quantitative proteomics to identify OGT targeting proteins, and finally identifying the function of Aurora Kinase B in targeting OGT to mitotic substrates and structures. Our expected contribution is significant because we expect to find insight into the regulation of OGT by mitotic targeting proteins and how these interactions are uncoupled in diseases such as cancer.

Public Health Relevance

Many solid tumors show aspects of aneuploidy, a phenotype characterized by multinucleated cells. Gain of function of the O-GlcNAc transferase enzyme causes aneuploidy. The research proposed in this grant will provide significant biological information on how 0-GlcNAc transferase regulates mitosis and how alterations in OGT targeting can lead to the development of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
9P20GM104936-06
Application #
8480366
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$226,500
Indirect Cost
$76,500
Name
University of Kansas
Department
Type
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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