Stephen R. Hann, Ph.D.

Professor

steve.hann@vanderbilt.edu
Faculty Appointments
Professor of Cell and Developmental Biology
Education
Ph.D., Biochemistry, University of California, Riverside, CaliforniaA.B., Biochemistry, University of California, Berkeley, California
Office Address
B-2317 Medical Center North
TN 8240
Research Description
Our principal research interest focuses on the regulation and function of the oncogene and transcriptional regulator, MYC. Oncogenic MYC is thought to be a driving force in up to 70% of human cancers. Alterations of the MYC gene are found associated with several types of tumors in several human cancers, including lymphoma, colon, breast and lung cancers. Using a combination of molecular and biochemical techniques, we are investigating the complex role of 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 cofactors that control MYC function through direct interaction. We identified two novel binding proteins, the tumor suppressor ARF and nucleophosmin, which have opposite effects on MYC. ARF appears to negatively affect MYC transformation by controlling MYC-induced apoptosis through a new mechanism. In contrast, nucleophosmin is necessary for the ability of MYC to transform cells efficiently. Understanding the mechanism and functional consequences of these interactions will allow us to develop effective therapeutic approaches to inhibit MYC-induced tumorigenesis. We are also continuing to investigate the mechanism of MYC transcriptional activity, including the identification of a novel transactivation domain in MYC, target genes that mediate MYC function and the role of MYC post-translational modifications, proteolysis and localization.
Research Keywords
Our principal research interest focuses on the regulation and function of the oncogene and transcriptional regulator, MYC. Oncogenic MYC is thought to be a driving force in up to 70% of human cancers.
Publications
Broadus MR, Yew PR, Hann SR, Lee E. Small-molecule high-throughput screening utilizing Xenopus egg extract. Methods Mol. Biol. 2015; 1263: 63-73. PMID: 25618336, PMCID: PMC4492114, DOI: 10.1007/978-1-4939-2269-7_5, ISSN: 1940-6029.

Hann SR. MYC cofactors: molecular switches controlling diverse biological outcomes. Cold Spring Harb Perspect Med. 2014 Sep; 4(9): a014399. PMID: 24939054, PMCID: PMC4143105, PII: cshperspect.a014399, DOI: 10.1101/cshperspect.a014399, ISSN: 2157-1422.

Sekhar KR, Benamar M, Venkateswaran A, Sasi S, Penthala NR, Crooks PA, Hann SR, Geng L, Balusu R, Abbas T, Freeman ML. Targeting nucleophosmin 1 represents a rational strategy for radiation sensitization. Int. J. Radiat. Oncol. Biol. Phys [print-electronic]. 2014 Aug 8/1/2014; 89(5): 1106-14. PMID: 25035215, PMCID: PMC4105849, PII: S0360-3016(14)00461-1, DOI: 10.1016/j.ijrobp.2014.04.012, ISSN: 1879-355X.

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.

Zhang Q, Spears E, Boone DN, Li Z, Gregory MA, Hann SR. Domain-specific c-Myc ubiquitylation controls c-Myc transcriptional and apoptotic activity. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2013 Jan 1/15/2013; 110(3): 978-83. PMID: 23277542, PMCID: PMC3549076, PII: 1208334110, DOI: 10.1073/pnas.1208334110, ISSN: 1091-6490.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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. Specialized gene expression in the epididymis. Journal of Andrology. 1995; 16: 379-83.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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., 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.