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.
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.
|Wang, Huizhen; Luo, Jinping; Carlton, Carol et al. (2017) Sperm-oocyte contact induces outside-in signaling via PYK2 activation. Dev Biol 428:52-62|
|Padró, Mercè; Louie, Raymond J; Lananna, Brian V et al. (2017) Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells. BMC Cancer 17:203|
|New, Jacob; Arnold, Levi; Ananth, Megha et al. (2017) Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target. Cancer Res 77:6679-6691|
|Rogers, Robert S; Tungtur, Sudheer; Tanaka, Tomohiro et al. (2017) Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice. Front Neurosci 11:473|
|Lui, Asona J; Geanes, Eric S; Ogony, Joshua et al. (2017) IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Cancer Lett 399:29-43|
|Tan, Ee Phie; Duncan, Francesca E; Slawson, Chad (2017) The sweet side of the cell cycle. Biochem Soc Trans 45:313-322|
|Wilson, C; Qiu, L; Hong, Y et al. (2017) The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene 36:2565-2576|
|Chen, Lei; Zhao, Lin; Samanta, Anweshan et al. (2017) STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPK?/mTOR axis. PLoS One 12:e0179835|
|Jasti, Susmita; Farahbakhsh, Mina; Nguyen, Sean et al. (2017) Immune response to a model shared placenta/tumor-associated antigen reduces cancer risk in parous mice. Biol Reprod 96:134-144|
|Samanta, Saheli; Rajasingh, Sheeja; Cao, Thuy et al. (2017) Epigenetic dysfunctional diseases and therapy for infection and inflammation. Biochim Biophys Acta 1863:518-528|
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