Demystifying Medicine

Speaker Profile

John A. Hanover, Ph.D.
Laboratory of Cell Biochemistry and Biology, Chief
NIDDK, National Institutes of Health
Building 8, Room 402
Bethesda, MD 20892-0851
Telephone: (301) 496-0943
E-mail: jah@helix.nih.gov
B.S., University of Tulsa, 1976
Ph.D., Johns Hopkins University School of Medicine, 1981

Research Statement

Our laboratory focuses on (1) the mechanism of nuclear transport and (2) the molecular features of a novel, glycan-dependent, signal transduction cascade. The nuclear transport of transcription factors, nuclear kinases, steroid hormone receptors, and replication factors often serves a critical regulatory function. We are examining the mechanisms of nuclear import, export, and subnuclear targeting. We identified a novel nuclear transport pathway involving calmodulin. This pathway has been shown to play a role in mammalian sex determination and stem cell differentiation. We are identifying additional components of this pathway using yeast genetics and chemical biology approaches. The nuclear pore complex (NPC) mediates the transport of mRNA and proteins across the nuclear envelope. Many components of the nuclear pore are modified by a novel modification: O-linked N-acetylglucosamine (O-linked GlcNAc). The modification also occurs on transcription factors and certain oncogenes and tumor suppressors. Current evidence suggests that the O-linked GlcNAc transferase mediates a novel glycan-dependent signal transduction pathway. We have molecularly cloned and characterized the human O-linked GlcNAc transferase responsible for glycosylating nuclear pore proteins. This enzyme is expressed as differentially targeted isoforms in man and is localized to both the nucleus and the mitochondria. When expressed in E. coli, the human O-linked GlcNAc transferase is catalytically active. We recently solved the X-Ray structure of the substrate recognition domain of OGT and we are beginning to understand how it recognizes its many intracellular targets. Although the enzyme is found in a number of target tissues, it is most highly expressed in human pancreatic beta cells, consistent with a role in glucose-sensing. Based on its substrate specificity and molecular features, we have proposed that O-linked GlcNAc transferase is the terminal step in a glucose-responsive pathway that becomes disregulated in diabetes mellitus (NIDDM). The enzyme catalyzing O-GlcNAc removal, O-GlcNAcase, has also been identified, expressed and shown to exist as differentially targeted isoforms in man. We are also using the genetically amenable C. elegans model to examine the physiological impact of the enzymes of O-GlcNAc cycling. Using reverse genetics, knockout, and other transgenic models we are currently exploring the role of these essential genes in signal transduction and pathogenesis of diabetes mellitus.

Selected Publications

1. Hajduch J, Nam G, Kim EJ, Frohlich R, Hanover JA, Kirk KL. A convenient synthesis of the C-1-phosphonate analogue of UDP-GlcNAc and its evaluation as an inhibitor of O-linked GlcNAc transferase (OGT). Carbohydr Res, 2007.
2. Wesierska-Gadek J, Klima A, Ranftler C, Komina O, Hanover J, Invernizzi P, Penner E. Characterization of the antibodies to p62 nucleoporin in primary biliary cirrhosis using human recombinant antigen. J Cell Biochem, 2007.
3. Kim EJ, Amorelli B, Abdo M, Thomas CJ, Love DC, Knapp S, Hanover JA. Distinctive Inhibition of O-GlcNAcase Isoforms by an alpha-GlcNAc Thiolsulfonate. J Am Chem Soc, 2007.
4. Kim CS, Furuya F, Ying H, Kato Y, Hanover JA, Cheng SY. Gelsolin: A novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer. Endocrinology(148): 1306-12, 2007.
5. Furuya F, Guigon CJ, Zhao L, Lu C, Hanover JA, Cheng SY. Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling. Mol Cell Biol(27): 6116-26, 2007.
6. Knapp S, Abdo M, Ajayi K, Huhn RA, Emge TJ, Kim EJ, Hanover JA. Tautomeric modification of GlcNAc-thiazoline. Org Lett(9): 2321-4, 2007.
7. Hanover JA, Love DC, Deangelis N, O'Kane ME, Lima-Miranda R, Schulz T, Yen YM, Johnson RC, Prinz WA. The High Mobility Group Box Transcription Factor Nhp6Ap Enters the Nucleus by a Calmodulindependent, Ran-independent Pathway. J Biol Chem(282): 33743-51, 2007.
8. Zhao Y, Conze DB, Hanover JA, Ashwell JD. Tumor necrosis factor receptor 2 (TNFR2) signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates MAP kinase signaling. J Biol Chem , 2007.
9. Ying H, Furuya F, Zhao L, Araki O, West BL, Hanover JA, Willingham MC, Cheng SY. Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. J Clin Invest(116): 2972-84, 2006.
10. Furuya F, Hanover JA, Cheng SY. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. Proc Natl Acad Sci U S A (103): 1780-5, 2006.

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