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O-GlcNAc cycling is a key regulator of Signaling, chromatin structure and morphogenesis

O-GlcNAc cycling is a key regulator of Signaling, chromatin structure and morphogenesis. By interacting with other epigenetic effectors, the nutrient-responsive O-GlcNAc cycling pathway may exert transgenerational influences.

Drosophila Polytene chromosomes visualizing sites of O-GlcNAc and RNA polymerase II at discrete chromosomal sites

Drosophila Polytene chromosomes visualizing sites of O-GlcNAc and RNA polymerase II at discrete chromosomal sites including those associated with polycomb repression.

C. elegans daf16::GFP reporter in wildtype (N2) and ogt-1 strains

C. elegans daf16::GFP reporter in wildtype (N2) and ogt-1 strains. The daf-16 reporter is localized to the nucleus in ogt-1 even in the absence of stress. In C. elegans, O-GlcNAc cycling regulates Stress, Immunity, and Longevity.

John A. Hanover, Ph.D.


Chief, LCMB, NIDDK

LCBB
LABORATORY OF CELL & MOLECULAR BIOLOGY
NIDDK, National Institutes of Health
Building 8 , Room B127
8 Center Dr.
Bethesda, MD 20814
Tel: 301-496-0943
Fax: 301-496-9431
Email: jah@helix.nih.gov

John A Hanover, Ph.D.

Research Website:


Education / Previous Training and Experience:
B.S., University of Tulsa, 1976
Ph.D., Johns Hopkins University School of Medicine, 1981


Research Statement:
Our laboratory focuses on (1) the molecular features of a novel, glycan-dependent, signal transduction cascade and (2) the mechanism of nuclear transport. 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.  Our studies further suggest that O-GlcNAc cycling plays a key role in the regulation of chromatin structure and may be a key player in  epigenetic reprogramming in response to nutrition and other environmental influences (See figure at right).


Selected Publications:
Mondoux, M. A., Love, D. C., Ghosh, S. K., Fukushige, T., Bond, M., Weerasinghe, G. R., Hanover, J. A., and Krause, M. W. (2011) O-linked-N-acetylglucosamine cycling and insulin signaling are required for the glucose stress response in Caenorhabditis elegans. Genetics 188, 369-382

Hanover, J. A. (2011) A versatile sugar transferase makes the cut. Cell 144, 321-323

Keembiyehetty, C. N., Krzeslak, A., Love, D. C., and Hanover, J. A. (2011) A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome. J Cell Sci 124, 2851-2860

Kim, E. J., Love, D. C., Darout, E., Abdo, M., Rempel, B., Withers, S. G., Rablen, P. R., Hanover, J. A., and Knapp, S. (2010) OGA inhibition by GlcNAc-selenazoline. Bioorg Med Chem 18, 7058-7064

Hanover, J. A., Krause, M. W., and Love, D. C. (2010) The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim Biophys Acta 1800, 80-95

Sekine, O., Love, D. C., Rubenstein, D. S., and Hanover, J. A. (2010) Blocking O-linked GlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. J Biol Chem 285, 38684-38691

Hanover, J. A. (2010) Epigenetics gets sweeter: O-GlcNAc joins the “histone code”. Chem Biol 17, 1272-1274

Love, D. C., Krause, M. W., and Hanover, J. A. (2010) O-GlcNAc cycling: emerging roles in development and epigenetics. Semin Cell Dev Biol 21, 646-654

Love, D. C., Ghosh, S., Mondoux, M. A., Fukushige, T., Wang, P., Wilson, M. A., Iser, W. B., Wolkow, C. A., Krause, M. W., and Hanover, J. A. (2010) Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity. Proc Natl Acad Sci U S A 107, 7413-7418

Lazarus, B. D., Love, D. C., and Hanover, J. A. (2009) O-GlcNAc cycling: implications for neurodegenerative disorders. Int J Biochem Cell Biol 41, 2134-2146

Hanover, J. A., Love, D. C., and Prinz, W. A. (2009) Calmodulin-driven nuclear entry: trigger for sex determination and terminal differentiation. J Biol Chem 284, 12593-12597

Chen, S., Whetstine, J. R., Ghosh, S., Hanover, J. A., Gali, R. R., Grosu, P., and Shi, Y. (2009) The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span. Proc Natl Acad Sci U S A 106, 1496-1501

Krawczyk, E., Suprynowicz, F. A., Liu, X., Dai, Y., Hartmann, D. P., Hanover, J., and Schlegel, R. (2008) Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins. Am J Pathol 173, 682-688

Wesierska-Gadek, J., Klima, A., Ranftler, C., Komina, O., Hanover, J., Invernizzi, P., and Penner, E. (2008) Characterization of the antibodies to p62 nucleoporin in primary biliary cirrhosis using human recombinant antigen. J Cell Biochem 104, 27-37

Krawczyk, E., Hanover, J. A., Schlegel, R., and Suprynowicz, F. A. (2008) Karyopherin beta3: a new cellular target for the HPV-16 E5 oncoprotein. Biochem Biophys Res Commun 371, 684-688

Hajduch, J., Nam, G., Kim, E. J., Frohlich, R., Hanover, J. A., and Kirk, K. L. (2008) 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 343, 189-195

Furuya, F., Guigon, C. J., Zhao, L., Lu, C., Hanover, J. A., and Cheng, S. Y. (2007) Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling. Mol Cell Biol 27, 6116-6126

Hanover, J. A., Love, D. C., DeAngelis, N., O’Kane, M. E., Lima-Miranda, R., Schulz, T., Yen, Y. M., Johnson, R. C., and Prinz, W. A. (2007) The High Mobility Group Box Transcription Factor Nhp6Ap enters the nucleus by a calmodulin-dependent, Ran-independent pathway. J Biol Chem 282, 33743-33751

Zhao, Y., Conze, D. B., Hanover, J. A., and Ashwell, J. D. (2007) Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling. J Biol Chem 282, 7777-7782

Kim, C. S., Furuya, F., Ying, H., Kato, Y., Hanover, J. A., and Cheng, S. Y. (2007) Gelsolin: a novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer. Endocrinology 148, 1306-1312

Knapp, S., Abdo, M., Ajayi, K., Huhn, R. A., Emge, T. J., Kim, E. J., and Hanover, J. A. (2007) Tautomeric modification of GlcNAc-thiazoline. Org Lett 9, 2321-2324

Kim, E. J., Amorelli, B., Abdo, M., Thomas, C. J., Love, D. C., Knapp, S., and Hanover, J. A. (2007) Distinctive inhibition of O-GlcNAcase isoforms by an alpha-GlcNAc thiolsulfonate. J Am Chem Soc 129, 14854-14855

Ying, H., Furuya, F., Zhao, L., Araki, O., West, B. L., Hanover, J. A., Willingham, M. C., and Cheng, S. Y. (2006) Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. J Clin Invest 116, 2972-2984

Lazarus, B. D., Love, D. C., and Hanover, J. A. (2006) Recombinant O-GlcNAc transferase isoforms: identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology 16, 415-421

Kim, E. J., Kang, D. O., Love, D. C., and Hanover, J. A. (2006) Enzymatic characterization of O-GlcNAcase isoforms using a fluorogenic GlcNAc substrate. Carbohydr Res 341, 971-982

Furuya, F., Hanover, J. A., and Cheng, S. Y. (2006) Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. Proc Natl Acad Sci U S A 103, 1780-1785

Perreira, M., Kim, E. J., Thomas, C. J., and Hanover, J. A. (2006) Inhibition of O-GlcNAcase by PUGNAc is dependent upon the oxime stereochemistry. Bioorg Med Chem 14, 837-846

Forsythe, M. E., Love, D. C., Lazarus, B. D., Kim, E. J., Prinz, W. A., Ashwell, G., Krause, M. W., and Hanover, J. A. (2006) Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc Natl Acad Sci U S A 103, 11952-11957

Kim, E. J., Perreira, M., Thomas, C. J., and Hanover, J. A. (2006) An O-GlcNAcase-specific inhibitor and substrate engineered by the extension of the N-acetyl moiety. J Am Chem Soc 128, 4234-4235

Lazarus, B. D., Roos, M. D., and Hanover, J. A. (2005) Mutational analysis of the catalytic domain of O-linked N-acetylglucosaminyl transferase. J Biol Chem 280, 35537-35544

Love, D. C., and Hanover, J. A. (2005) The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci STKE 2005, re13

Tang, D. C., Zhu, J., Liu, W., Chin, K., Sun, J., Chen, L., Hanover, J. A., and Rodgers, G. P. (2005) The hydroxyurea-induced small GTP-binding protein SAR modulates gamma-globin gene expression in human erythroid cells. Blood 106, 3256-3263

Wu, C. J., Conze, D. B., Li, X., Ying, S. X., Hanover, J. A., and Ashwell, J. D. (2005) TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. EMBO J 24, 1886-1898

Disbrow, G. L., Hanover, J. A., and Schlegel, R. (2005) Endoplasmic reticulum-localized human papillomavirus type 16 E5 protein alters endosomal pH but not trans-Golgi pH. J Virol 79, 5839-5846

Hanover, J. A., Forsythe, M. E., Hennessey, P. T., Brodigan, T. M., Love, D. C., Ashwell, G., and Krause, M. (2005) A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc Natl Acad Sci U S A 102, 11266-11271

Bar-Sinai, A., Bassa, N., Fischette, M., Gottesman, M. M., Love, D. C., Hanover, J. A., and Hochman, J. (2005) Mouse mammary tumor virus Env-derived peptide associates with nucleolar targets in lymphoma, mammary carcinoma, and human breast cancer. Cancer Res 65, 7223-7230

Jinek, M., Rehwinkel, J., Lazarus, B. D., Izaurralde, E., Hanover, J. A., and Conti, E. (2004) The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol 11, 1001-1007

Disbrow, G. L., Sunitha, I., Baker, C. C., Hanover, J., and Schlegel, R. (2003) Codon optimization of the HPV-16 E5 gene enhances protein expression. Virology 311, 105-114

Hanover, J. A., Yu, S., Lubas, W. B., Shin, S. H., Ragano-Caracciola, M., Kochran, J., and Love, D. C. (2003) Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch Biochem Biophys 409, 287-297

Love, D. C., Kochan, J., Cathey, R. L., Shin, S. H., and Hanover, J. A. (2003) Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J Cell Sci 116, 647-654

Zhang, M., Sun, M., Dwyer, N. K., Comly, M. E., Patel, S. C., Sundaram, R., Hanover, J. A., and Blanchette-Mackie, E. J. (2003) Differential trafficking of the Niemann-Pick C1 and 2 proteins highlights distinct roles in late endocytic lipid trafficking. Acta Paediatr Suppl 92, 63-73; discussion 45

Tsai, W. C., Bhattacharyya, N., Han, L. Y., Hanover, J. A., and Rechler, M. M. (2003) Insulin inhibition of transcription stimulated by the forkhead protein Foxo1 is not solely due to nuclear exclusion. Endocrinology 144, 5615-5622

Vocadlo, D. J., Hang, H. C., Kim, E. J., Hanover, J. A., and Bertozzi, C. R. (2003) A chemical approach for identifying O-GlcNAc-modified proteins in cells. Proc Natl Acad Sci U S A 100, 9116-9121

Chauhan, S. S., Liang, X. J., Su, A. W., Pai-Panandiker, A., Shen, D. W., Hanover, J. A., and Gottesman, M. M. (2003) Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines. Br J Cancer 88, 1327-1334

McClain, D. A., Lubas, W. A., Cooksey, R. C., Hazel, M., Parker, G. J., Love, D. C., and Hanover, J. A. (2002) Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci U S A 99, 10695-10699

Thakurta, A. G., Whalen, W. A., Yoon, J. H., Bharathi, A., Kozak, L., Whiteford, C., Love, D. C., Hanover, J. A., and Dhar, R. (2002) Crp79p, like Mex67p, is an auxiliary mRNA export factor in Schizosaccharomyces pombe. Mol Biol Cell 13, 2571-2584

Holaska, J. M., Black, B. E., Love, D. C., Hanover, J. A., Leszyk, J., and Paschal, B. M. (2001) Calreticulin Is a receptor for nuclear export. J Cell Biol 152, 127-140

Zhang, M., Dwyer, N. K., Neufeld, E. B., Love, D. C., Cooney, A., Comly, M., Patel, S., Watari, H., Strauss, J. F. r., Pentchev, P. G., Hanover, J. A., and Blanchette-Mackie, E. J. (2001) Sterol-modulated glycolipid sorting occurs in niemann-pick C1 late endosomes. J Biol Chem 276, 3417-3425

Zhang, M., Dwyer, N. K., Love, D. C., Cooney, A., Comly, M., Neufeld, E., Pentchev, P. G., Blanchette-Mackie, E. J., and Hanover, J. A. (2001) Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease. Proc Natl Acad Sci U S A 98, 4466-4471

Yoon, J. H., Love, D. C., Guhathakurta, A., Hanover, J. A., and Dhar, R. (2000) Mex67p of Schizosaccharomyces pombe interacts with Rae1p in mediating mRNA export. Mol Cell Biol 20, 8767-8782

Sweitzer, T. D., Love, D. C., and Hanover, J. A. (2000) Regulation of nuclear import and export. Curr Top Cell Regul 36, 77-94

Love, D. C., Sweitzer, T. D., and Hanover, J. A. (1998) Reconstitution of HIV-1 rev nuclear export: independent requirements for nuclear import and export. Proc Natl Acad Sci U S A 95, 10608-10613





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