John A. Hanover, Ph.D. : NIDDK

John A. Hanover, Ph.D.


LCBB
LABORATORY CELL BIOCHEMISTRY & BIOLOGY
NIDDK, National Institutes of Health
Building 8, Room B127
8 Center Dr.
Bethesda, MD 20892-0851
Tel: 301-496-0943
Fax: 301-496-9431
Email: jah@helix.nih.gov

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 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. [Full Text/Abstract]

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. [Full Text/Abstract]

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. [Full Text/Abstract]

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. [Full Text/Abstract]

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. [Full Text/Abstract]

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. [Full Text/Abstract]

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 Calmodulin-dependent, Ran-independent Pathway. J Biol Chem(282): 33743-51, 2007. [Full Text/Abstract]

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. [Full Text/Abstract]

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. [Full Text/Abstract]

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. [Full Text/Abstract]

11. Kim EJ, Perreira M, Thomas CJ, Hanover JA An O-GlcNAcase-Specific Inhibitor and Substrate Engineered by the Extension of the N-Acetyl Moiety. J Am Chem Soc (128): 4234-5, 2006. [Full Text/Abstract]

12. Forsythe ME, Love DC, Lazarus BD, Kim EJ, Prinz WA, Ashwell G, Krause MW, Hanover JA 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): 11952-7, 2006. [Full Text/Abstract]

13. Kim EJ, Kang DO, Love DC, Hanover JA Enzymatic characterization of O-GlcNAcase isoforms using a fluorogenic GlcNAc substrate. Carbohydr Res , 2006. [Full Text/Abstract]

14. Perreira M, Kim EJ, Thomas CJ, Hanover JA Inhibition of O-GlcNAcase by PUGNAc is dependent upon the oxime stereochemistry. Bioorg Med Chem (14): 837-46, 2006. [Full Text/Abstract]

15. Lazarus BD, Love DC, Hanover JA Recombinant O-GlcNAc transferase isoforms: identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology (16): 415-21, 2006. [Full Text/Abstract]

16. Hanover JA, Forsythe ME, Hennessey PT, Brodigan TM, Love DC, Ashwell G, Krause M 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): 11266-71, 2005. [Full Text/Abstract]

17. Disbrow GL, Hanover JA, Schlegel R Endoplasmic reticulum-localized human papillomavirus type 16 E5 protein alters endosomal pH but not trans-Golgi pH. J Virol (79): 5839-46, 2005. [Full Text/Abstract]

18. Bar-Sinai A, Bassa N, Fischette M, Gottesman MM, Love DC, Hanover JA, Hochman J Mouse mammary tumor virus Env-derived peptide associates with nucleolar targets in lymphoma, mammary carcinoma, and human breast cancer. Cancer Res (65): 7223-30, 2005. [Full Text/Abstract]

19. Lazarus BD, Roos MD, Hanover JA Mutational analysis of the catalytic domain of O-linked N-acetylglucosaminyl transferase. J Biol Chem (280): 35537-44, 2005. [Full Text/Abstract]

20. Love DC, Hanover JA The hexosamine signaling pathway: deciphering the "O-GlcNAc code". Sci STKE (2005): re13, 2005. [Full Text/Abstract]

21. Tang DC, Zhu J, Liu W, Chin K, Sun J, Chen L, Hanover JA, Rodgers GP The hydroxyurea-induced small GTP-binding protein SAR modulates gamma-globin gene expression in human erythroid cells. Blood (106): 3256-63, 2005. [Full Text/Abstract]

22. Wu CJ, Conze DB, Li X, Ying SX, Hanover JA, Ashwell JD TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. EMBO J (24): 1886-98, 2005. [Full Text/Abstract]

23. Jinek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol (11): 1001-7, 2004. [Full Text/Abstract]

24. Vocadlo DJ, Hang HC, Kim EJ, Hanover JA, Bertozzi CR A chemical approach for identifying O-GlcNAc-modified proteins in cells. Proc Natl Acad Sci U S A (100): 9116-21, 2003. [Full Text/Abstract]

25. Zhang M, Sun M, Dwyer NK, Comly ME, Patel SC, Sundaram R, Hanover JA, Blanchette-Mackie EJ 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, 2003. [Full Text/Abstract]

26. Tsai WC, Bhattacharyya N, Han LY, Hanover JA, Rechler MM Insulin inhibition of transcription stimulated by the forkhead protein Foxo1 is not solely due to nuclear exclusion. Endocrinology (144): 5615-22, 2003. [Full Text/Abstract]

27. Hanover JA, Yu S, Lubas WB, Shin SH, Ragano-Caracciola M, Kochran J, Love DC Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch Biochem Biophys (409): 287-97, 2003. [Full Text/Abstract]

28. Love DC, Kochan J, Cathey RL, Shin SH, Hanover JA Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J Cell Sci (116): 647-54, 2003. [Full Text/Abstract]

29. Chauhan SS, Liang XJ, Su AW, Pai-Panandiker A, Shen DW, Hanover JA, Gottesman MM Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines. Br J Cancer (88): 1327-34, 2003. [Full Text/Abstract]

30. McClain, DA, Lubas, WA, Cooksey, RC, Hazel, M, Parker, GJ, Love DC, Hanover, JA Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci U S A(99): 10695-9, 2002.

31. Thakurta AG, Whalen WA, Yoon JH, Bharathi A, Kozak L, Whiteford C, Love DC, Hanover JA, Dhar R Crp79p, like Mex67p, is an auxiliary mRNA export factor in Schizosaccharomyces pombe. Mol Biol Cell (13): 2571-84, 2002. [Full Text/Abstract]

32. Zhang M, Liu P, Dwyer NK, Christenson LK, Fujimoto T, Martinez F, Comly M, Hanover JA, Blanchette-Mackie EJ, Strauss JF 3rd MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria. J Biol Chem (277): 33300-10, 2002. [Full Text/Abstract]

33. Lin HM, Kaneshige M, Zhao L, Zhang X, Hanover JA, Cheng SY An isoform of branched-chain aminotransferase is a novel co-repressor for thyroid hormone nuclear receptors. J Biol Chem (276): 48196-205, 2001. [Full Text/Abstract]

34. Holaska JM, Black BE, Love DC, Hanover JA, Leszyk J, Paschal BM Calreticulin Is a receptor for nuclear export. J Cell Biol (152): 127-40, 2001. [Full Text/Abstract]

35. Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ, Hanover JA Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease. Proc Natl Acad Sci U S A (98): 4466-71, 2001. [Full Text/Abstract]

36. Hanover JA Glycan-dependent signaling: O-linked N-acetylglucosamine. FASEB J (15): 1865-76, 2001. [Full Text/Abstract]

37. Zhang M, Dwyer NK, Neufeld EB, Love DC, Cooney A, Comly M, Patel S, Watari H, Strauss JF 3rd, Pentchev PG, Hanover JA, Blanchette-Mackie EJ Sterol-modulated glycolipid sorting occurs in niemann-pick C1 late endosomes. J Biol Chem (276): 3417-25, 2001. [Full Text/Abstract]

38. Cui Y, Li M, Walton KD, Sun K, Hanover JA, Furth PA, Hennighausen L The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue. Genomics (78): 129-34, 2001. [Full Text/Abstract]

39. Bustamante JO, Michelette ER, Geibel JP, Dean DA, Hanover JA, McDonnell TJ Calcium, ATP and nuclear pore channel gating. Pflugers Arch (439): 433-44, 2000. [Full Text/Abstract]

40. Bustamante JO, Michelette ER, Geibel JP, Hanover JA, McDonnell TJ, Dean DA Dendrimer-assisted patch-clamp sizing of nuclear pores. Pflugers Arch (439): 829-37, 2000. [Full Text/Abstract]

41. Lubas WA, Hanover JA Functional expression of O-linked GlcNAc transferase. Domain structure and substrate specificity. J Biol Chem (275): 10983-8, 2000. [Full Text/Abstract]

42. Dace A, Zhao L, Park KS, Furuno T, Takamura N, Nakanishi M, West BL, Hanover JA, Cheng S Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors. Proc Natl Acad Sci U S A (97): 8985-90, 2000. [Full Text/Abstract]

43. Yoon JH, Love DC, Guhathakurta A, Hanover JA, Dhar R Mex67p of Schizosaccharomyces pombe interacts with Rae1p in mediating mRNA export. Mol Cell Biol (20): 8767-82, 2000. [Full Text/Abstract]

44. Soukharev S, Berlin W, Hanover JA, Bethke B, Sauer B Organization of the mouse ASGR1 gene encoding the major subunit of the hepatic asialoglycoprotein receptor. Gene (241): 233-40, 2000. [Full Text/Abstract]

45. Sweitzer TD, Love DC, Hanover JA Regulation of nuclear import and export. Curr Top Cell Regul (36): 77-94, 2000. [Full Text/Abstract]

46. Roos MD, Hanover JA Structure of O-linked GlcNAc transferase: mediator of glycan-dependent signaling. Biochem Biophys Res Commun (271): 275-80, 2000. [Full Text/Abstract]

47. Kurys G, Tagaya Y, Bamford R, Hanover JA, Waldmann TA The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15. J Biol Chem (275): 30653-9, 2000. [Full Text/Abstract]


Page last updated: December 15, 2008

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