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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 

Stephen R. Hann, Ph.D.

Professor of Cell and Developmental Biology
Researcher

Contact Information:

Vanderbilt University Medical Center
B-2324 Medical Center North
Nashville, TN 37232-2175
615-343-434r

Research Description

Our principal research interest focuses on the regulation and function of the oncogene and transcriptional regulator, c-myc. Oncogenic c-Myc is thought to be a driving force in up to 70% of human cancers. Alterations of the c-myc gene are found associated with several types of tumors in several human cancers, including lymphoma and colon, breast and lung cancers. Using a combination of molecular and biochemical techniques, we are investigating the complex role of c-Myc as transcriptional regulator, and its biological roles in cellular proliferation, apoptosis and oncogenesis both in culture and in animals. Our current focus is on proteins that control c-Myc function through direct interaction. We identified two novel binding proteins, the tumor suppressor ARF and nucleophosmin, which have opposite effects on c-Myc. ARF appears to negatively affect c-Myc transformation by controlling c-Myc-induced apoptosis through a new mechanism. In contrast, nucleophosmin is necessary for the ability of c-Myc to transform cells efficiently. Understanding the mechanism and functional consequences of these interactions will allow us to develop effective therapeutic approaches to inhibit c-Myc-induced tumorigenesis. We are also continuing to investigate the mechanism of c-Myc transcriptional activity, including the identification of target genes that mediate c-Myc function and the role of c-Myc post-translational modifications, proteolysis and localization.

Publications
  • Li Z, Hann SR. Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. Oncogene [print-electronic]. 2013 Apr 4/11/2013; 32(15): 1988-94. PMID: 22665062, PMCID: PMC3855075, PII: onc2012227, DOI: 10.1038/onc.2012.227, ISSN: 1476-5594.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/22665062.
  • Boone DN, Hann SR. The Myc-ARF-Egr1 pathway: unleashing the apoptotic power of c-Myc [editorial]. Cell Cycle. 2011 Jul 7/1/2011; 10(13): 2043-4. PMID: 21709445, PMCID: PMC3234342, PII: 15711, ISSN: 1551-4005.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21709445.
  • Boone DN, Qi Y, Li Z, Hann SR. Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2011 Jan 1/11/2011; 108(2): 632-7. PMID: 21187408, PMCID: PMC3021028, PII: 1008848108, DOI: 10.1073/pnas.1008848108, ISSN: 1091-6490.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21187408.
  • Li Z, Hann SR. The Myc-nucleophosmin-ARF network: a complex web unveiled. Cell Cycle [print-electronic]. 2009 Sep 9/1/2009; 8(17): 2703-7. PMID: 19652540, PMCID: PMC3234343, PII: 9418, ISSN: 1551-4005.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19652540.
  • Li Z, Boone D, Hann SR. Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2008 Dec 12/2/2008; 105(48): 18794-9. PMID: 19033198, PMCID: PMC2596228, PII: 0806879105, DOI: 10.1073/pnas.0806879105, ISSN: 1091-6490.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19033198.
  • Hann SR. Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function. Semin. Cancer Biol [print-electronic]. 2006 Aug; 16(4): 288-302. PMID: 16938463, PII: S1044-579X(06)00070-8, DOI: 10.1016/j.semcancer.2006.08.004, ISSN: 1044-579X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16938463.
  • Vaknin UA, Hann SR. The alpha1 subunit of GABAA receptor is repressed by c-myc and is pro-apoptotic. J. Cell. Biochem. 2006 Apr 4/1/2006; 97(5): 1094-103. PMID: 16294320, DOI: 10.1002/jcb.20708, ISSN: 0730-2312.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16294320.
  • Gregory MA, Qi Y, Hann SR. The ARF tumor suppressor: keeping Myc on a leash. Cell Cycle [print-electronic]. 2005 Feb; 4(2): 249-52. PMID: 15655352, PII: 1491, ISSN: 1551-4005.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15655352.
  • Hsia, N., Brousal, J., Hann, S.R., and Cornwall, G.A.. Germ-cell specific expression of a cystatin-related epididymal spermatogenic (CRES) promoter-CAT transgene. J. of Andrology. 2005; 26: 249-57.
  • Qi Y, Gregory MA, Li Z, Brousal JP, West K, Hann SR. P19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature [print-electronic]. 2004 Oct 10/7/2004; 431(7009): 712-7. PMID: 15361884, PII: nature02958, DOI: 10.1038/nature02958, ISSN: 1476-4687.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15361884.
  • Domina, A.M., Vrana, J.A., Gregory, M.A., Hann, S.R., and Craig, R.C.. MCL 1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with okadaic acid or taxol. Oncogene. 2004; 8: 5301-15.
  • Gregory MA, Qi Y, Hann SR. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J. Biol. Chem [print-electronic]. 2003 Dec 12/19/2003; 278(51): 51606-12. PMID: 14563837, PII: M310722200, DOI: 10.1074/jbc.M310722200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/14563837.
  • Cornwall GA, Collis R, Xiao Q, Hsia N, Hann SR. B-Myc, a proximal caput epididymal protein, is dependent on androgens and testicular factors for expression. Biol. Reprod. 2001 Jun; 64(6): 1600-7. PMID: 11369584, ISSN: 0006-3363.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11369584.
  • Gregory MA, Xiao Q, Cornwall GA, Lutterbach B, Hann SR. B-Myc is preferentially expressed in hormonally-controlled tissues and inhibits cellular proliferation. Oncogene. 2000 Oct 10/5/2000; 19(42): 4886-95. PMID: 11039906, DOI: 10.1038/sj.onc.1203851, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11039906.
  • Claassen GF, Hann SR. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest. Proc. Natl. Acad. Sci. U.S.A. 2000 Aug 8/15/2000; 97(17): 9498-503. PMID: 10920185, PMCID: PMC16893, PII: 150006697, DOI: 10.1073/pnas.150006697, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10920185.
  • Niklinski J, Claassen G, Meyers C, Gregory MA, Allegra CJ, Kaye FJ, Hann SR, Zajac-Kaye M. Disruption of Myc-tubulin interaction by hyperphosphorylation of c-Myc during mitosis or by constitutive hyperphosphorylation of mutant c-Myc in Burkitt's lymphoma. Mol. Cell. Biol. 2000 Jul; 20(14): 5276-84. PMID: 10866684, PMCID: PMC85977, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10866684.
  • Chang DW, Claassen GF, Hann SR, Cole MD. The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals. Mol. Cell. Biol. 2000 Jun; 20(12): 4309-19. PMID: 10825194, PMCID: PMC85798, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10825194.
  • Gregory MA, Hann SR. C-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol. Cell. Biol. 2000 Apr; 20(7): 2423-35. PMID: 10713166, PMCID: PMC85426, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10713166.
  • Claassen GF, Hann SR. Myc-mediated transformation: the repression connection. Oncogene. 1999 May 5/13/1999; 18(19): 2925-33. PMID: 10378689, DOI: 10.1038/sj.onc.1202747, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10378689.
  • Lutterbach B, Hann SR. C-Myc transactivation domain-associated kinases: questionable role for map kinases in c-Myc phosphorylation. J. Cell. Biochem. 1999 Mar 3/15/1999; 72(4): 483-91. PMID: 10022608, PII: 10.1002/(SICI)1097-4644(19990315)72:4<483::AID-JCB4>3.0.CO;2-I, ISSN: 0730-2312.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10022608.
  • Greenberg, R., O'Hagan, R., Deng H., Xiao, Q., Hann, S., Adams, R., Lichtsteiner, S., Chin, L., Morin, G. and DePinho, R. Telomerase Reverse Transcriptase Gene is a Direct Target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene. 1999; 18: 1219-26.
  • Xiao Q, Claassen G, Shi J, Adachi S, Sedivy J, Hann SR. Transactivation-defective c-MycS retains the ability to regulate proliferation and apoptosis. Genes Dev. 1998 Dec 12/15/1998; 12(24): 3803-8. PMID: 9869633, PMCID: PMC317265, ISSN: 0890-9369.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9869633.
  • Spotts GD, Patel SV, Xiao Q, Hann SR. Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins. Mol. Cell. Biol. 1997 Mar; 17(3): 1459-68. PMID: 9032273, PMCID: PMC231871, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9032273.
  • Lutterbach B, Hann SR. Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation. Oncogene. 1997 Feb 2/27/1997; 14(8): 967-75. PMID: 9050996, DOI: 10.1038/sj.onc.1200920, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9050996.
  • Arsura, M., Deshpande, A., Hann, S., and Sonenshein, G. Varient Max protein, derived by alternative splicing, associates with c-myc in vivo and inhibits transactivation. Mol. Cell. Biol. 1995; 15: 6702-9.
  • Cornwall, G.A. and Hann, S. R. Transient appearance of the CRES protein during spermatogenesis and caput epididymal sperm maturation. Mol. Reprod. and Develop. 1995; 41: 37-46.
  • Cornwall, G.A. and Hann, S.R. Specialized gene expression in the epididymis. Journal of Andrology. 1995; 16: 379-83.
  • Hann SR. Methionine deprivation regulates the translation of functionally-distinct c-Myc proteins. Adv. Exp. Med. Biol. 1995; 375: 107-16. PMID: 7645422, ISSN: 0065-2598.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7645422.
  • Hoang, A., Lutterbach, B., Lewis, B., Yano, T., Chou, Y., Barrett, J. Raffeld, M., Hann, S. and Dang, C. Increased transfon-ning activity of lymphoma-derived MYC mutant alleles results from defective regulation by plO7 and altered phosphorylation of the MYC transactivation domain. Mol. Cell. Biol. 1995; 15: 4031-42.
  • Hann SR, Dixit M, Sears RC, Sealy L. The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site. Genes Dev. 1994 Oct 10/15/1994; 8(20): 2441-52. PMID: 7958908, ISSN: 0890-9369.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7958908.
  • Lutterbach B, Hann SR. Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis. Mol. Cell. Biol. 1994 Aug; 14(8): 5510-22. PMID: 8035827, PMCID: PMC359071, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8035827.
  • Hann SR. Regulation and function of non-AUG-initiated proto-oncogenes. Biochimie. 1994; 76(9): 880-6. PMID: 7880905, PII: 0300-9084(94)90190-2, ISSN: 0300-9084.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7880905.
  • Hann, S.R. Regulation and function of non-AUG-initiated proto-oncogenes. Biochiinie. 1994; 76: 880-6.
  • Davis, A.C., Wims, M., Spotts, G.D., Hann, S.R. and Bradley, A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygote embryos and reduced fertility in heterozygous female mice. Genes and Development. 1993; 7: 671-82.
  • Cornwall GA, Orgebin-Crist MC, Hann SR. Expression of an endogenous murine leukemia virus-related proviral sequence is androgen regulated and primarily restricted to the epididymis/vas deferens and oviduct/uterus. Biol. Reprod. 1992 Oct; 47(4): 665-75. PMID: 1327210, ISSN: 0006-3363.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1327210.
  • Cornwall GA, Orgebin-Crist MC, Hann SR. The CRES gene: a unique testis-regulated gene related to the cystatin family is highly restricted in its expression to the proximal region of the mouse epididymis. Mol. Endocrinol. 1992 Oct; 6(10): 1653-64. PMID: 1280328, DOI: 10.1210/mend.6.10.1280328, ISSN: 0888-8809.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1280328.
  • Cornwall GA, Orgebin-Crist MC, Hann SR. Differential expression of the mouse mitochondrial genes and the mitochondrial RNA-processing endoribonuclease RNA by androgens. Mol. Endocrinol. 1992 Jul; 6(7): 1032-42. PMID: 1508219, DOI: 10.1210/mend.6.7.1508219, ISSN: 0888-8809.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1508219.
  • Hann SR, Sloan-Brown K, Spotts GD. Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation. Genes Dev. 1992 Jul; 6(7): 1229-40. PMID: 1628829, ISSN: 0890-9369.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1628829.
  • Robinson-Benion C, Salhany KE, Hann SR, Holt JT. Antisense inhibition of c-myc expression reveals common and distinct mechanisms of growth inhibition by TGF beta and TNF alpha. J. Cell. Biochem. 1991 Feb; 45(2): 188-95. PMID: 2055946, DOI: 10.1002/jcb.240450210, ISSN: 0730-2312.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2055946.
  • Spotts GD, Hann SR. Enhanced translation and increased turnover of c-myc proteins occur during differentiation of murine erythroleukemia cells. Mol. Cell. Biol. 1990 Aug; 10(8): 3952-64. PMID: 2196440, PMCID: PMC360906, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2196440.
  • Levine, R.A., Seshadri, T., Hann, S.R. and Campisi, J. Posttranscriptioal changes in growth factor- inducible gene regulation caused by antiproliferative interferons. Gene Regulation. 1990; 1: 215-26.
  • Hann, S.R., King, M.W., Bentley, D.L., Anderson, C.W. and Eisemnan, R.N. A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas. Cell. 1988; 52: 185-95.
  • Eisenman, R.N., Tachibana, C.Y., Abrams, H.D., Hann, S.R.. V-myc and c-myc-encoded proteins are associated with the nuclear matrix. Mol. Cell. Biol. 1985; 5: 114-26.
  • Hann, S.R., Thompson, C.B., Eiserunan, R.N. C-myc oncogene protein synthesis is independent of the cell cycle in human and avian cells. Nature. 1985; 314: 366-9.
  • Hann, S.R., Eisemnan, R.N. Proteins encoded by the human c-myc oncogene: Differential expression in neoplastic cells. Mol Cell Biol. 1984; 4: 2486-97.
  • Hann, S. R., Abrams, H. D., Rohrschneider, L. R., Eisenman, R. N. Proteins encoded by the v-myc and c-myc oncogenes: Identification and localization in acute leukemia virus transformants and bursal lymphoma cell lines. Cell. 1983; 34: 789-98.