Chad Slawson, Ph.D.

Assistant Professor
Department of Biochemistry and Molecular Biology

Ph.D., University of South Florida, 2002
Postdoctoral, John Hopkins School of Medicine, 2002-2010


cslawson@kumc.edu

Research Focus: Understand how the O-GlcNAc post-translational modification regulates cellular function.

What is O-GlcNAc?  O-GlcNAc is the addition of a single N-acetyl-glucosamine residue to serine/threonine residues of proteins found in the cytoplasm or nucleus (O-GlcNAcylation).  Unlike extracellular glycosylation, the sugar residue is not elongated into complex oligosaccharides and is added or removed dynamically in response to cellular stimuli by a single O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) respectively. O-GlcNAc is involved in many cellular processes such as nutrient sensing, stress response, transcription, translation, cell signaling, and cell cycle regulation.

O-GlcNAc Regulates Mitosis: All dividing cells must undergo mitosis, the process in which a eukaryotic cell separates into two daughter cells containing identical sets of chromosomes surrounded by a newly formed nucleus while partitioning cellular components such as organelles and cytoplasm equally to the two daughter cells.  This elaborate process is coordinated by hundreds of proteins, and many of these proteins are regulated by post-translational modifications.  O-GlcNAcylation regulates the function, localization, degradation, and protein interactions of these proteins. Interestingly, elevations in the expression of OGT or OGA cause aneuploidy, which is an abnormal number of chromosomes in the daughter cells. This is partially due to the fact that OGT localizes to mitotic structures such as the spindle and midbody during mitosis and altered O-GlcNAcylation at these sites promote aneuploidy. 


O-GlcNAc Regulates Mitochondrial Function: Virtually every cell in a multi-cellular organism requires mitochondria to generate ATP or metabolic precursors; unfortunately, alteration of mitochondrial function is synonymous with disease Genetic mutations of mitochondrial proteins alone cannot explain the breath and scope of mitochondrial related dysfunction. Rather, post-translational modifications (PTM) provide mitochondrial proteins with the molecular diversity needed to respond rapidly to changing environmental conditions.  For example, acetylation of proteins involved in the electron transport chain, Krebs cycle, and fatty acid oxidation impair function and alter the metabolite production in the mitochondrial.  However, the O-GlcNAc post-translational modification also regulates mitochondrial function.  Alterations in the expression of OGT or OGA have a profound effect on mitochondrial function.  The expression of mitochondrial nuclear encoded genes is dramatically altered with significant expression changes to proteins involved in the TCA cycle and respiration.  Importantly, these changes depress the rate of respiration suggesting a critical role for O-GlcNAc in regulating cellular energetics.

O-GlcNAc Regulates Transcription: Not surprisingly, post-translational modifications are key regulators of gene transcription.  For example, O-GlcNAc transferase (OGT) is part of the polycomb repressor complex, and OGT null mutations in Drosophila lead to altered HOX gene expression.  O-GlcNAc plays a pivotal role in regulating the human g-globin genes by organizing chromatin-remodeling complexes.  One mode of g-globin silencing occurs at the GATA binding sites located at -566 or -567 relative to the Ag-globin or Gg-globin CAP sites respectively, and is mediated through the DNA binding moiety of GATA-1 and its recruitment of co-repressor partners, FOG-1 and Mi2 (NuRD complex; Harju-Baker et al., 2008). Both OGT and OGA associate with the g-globin promoter and alterations the rate of O-GlcNAc addition and removal control expression of the g-globin.  These gene expression changes likely are mediated by changes in the O-GlcNAcylation status of Mi2.

Selected Publications

Tan E., Villar M.T., E L., Lu J., Selfridge J.E., Artigues A., Swerdlow R.H., and Slawson C. (2014) Altering O-linked β-N-Acetylglucosamine cycling disrupts mitochondrial function.  J. Biol. Chem. 289: 14719-14730. 

Tan, E., Caro, S., Potnis, A., Lanza, C., and Slawson, C. (2013) O-linked N-acetylglucosamine cycling regulates mitotic spindle organization. J. Biol. Chem. 288: 27085-27099. 

Gao, X., Wang, X., Pham, T.H., Feuerbacher, L.A., Lubos, M.L., Huang, M., Olsen, R., Mushegian, A., Slawson, C., and Hardwidge, P.R. (2013) NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-κB activation. Cell Host & Microbe 13:1-13

Slawson, C., and Hart, GW. (2011) O-GlcNAc signaling: implications for cancer cell biology.  Nat. Rev. Cancer, 11: 678-684. 

Wang, Z., Udeshi, N.D., Slawson, C, Compton, P.D., Sakabe, K., Cheung, W.D., Shabanowitz, J., Hunt, D.F., and Hart G.W. (2010) O-GlcNAcylation Regulates Mitotic Spindle/Midbody Phosphorylation. Sci Signal 3, ra2.

Li, X., Molina, H., Huang, H., Zhang, Y-Y., Liu, M., Qian, S-W., Slawson, C., Dias, W.B., Pandey, A., Hart, G.W., Lane, M.D., and  Tang, Q-Q. (2009) O-Linked N-acetylglucosamine modification on C/EBPb: role during adipocyte differentiation. J. Biol. Chem. 284:19248-19254

Slawson, C. Lakshmanan, T., Knapp, S., and Hart, G.W.  (2008) A mitotic GlcNAcylation/Phosphorylation signaling complex alters the post-translational state of the cytoskeletal protein vimentin.  Mol. Biol. Cell 19:4130-4140. 

Slawson, C., Zachara, N.E., Vosseller, K., Cheung, W.D., Lane, M.D., and Hart, G.W. (2005) Perturbations in O-linked b-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J. Biol. Chem. 280:32944-32956.

Slawson, C., Shafii, S., Amburgey, J., and Potter, R.L.  (2002) Characterization of the O-GlcNAc protein modification in Xenopus laevis oocytes during oogenesis and progesterone stimulated maturation.  Biochim. Biophys. Acta 1573:121-129.

Slawson, C., Pidala, J., and Potter, R.L. (2001) Increased N-Acetyl-b-glucosaminidase activity in primary breast carcinomas corresponds to a decrease in N-acetylglucosamine containing proteins.  Biochim Biophys Acta 1537:147-57.

  

Last modified: Jun 25, 2014

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Chad Slawson, Ph.D.
Assistant Professor

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