Stephen R. Hann, Ph.D.
Vanderbilt University Medical Center
B-2324 Medical Center North
Nashville, TN 37232-2175
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.
- Li, Z, Hann, SR Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. Oncogene, 2012.
- 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, 108(2), 632-7, 2011.
- Boone, DN, Hann, SR The Myc-ARF-Egr1 pathway: unleashing the apoptotic power of c-Myc. Cell Cycle, 10(13), 2043-4, 2011.
- Li, Z, Hann, SR The Myc-nucleophosmin-ARF network: a complex web unveiled. Cell Cycle, 8(17), 2703-7, 2009.
- 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, 105(48), 18794-9, 2008.
- Hann, SR Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function. Semin Cancer Biol, 16(4), 288-302, 2006.
- Vaknin, UA, Hann, SR The alpha1 subunit of GABA(A) receptor is repressed by c-Myc and is pro-apoptotic. J Cell Biochem, 97 (5)1094-103, 2006.
- 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 , 26249-257, 2005.
- Gregory, MA, Qi, Y, Hann, SR The ARF tumor suppressor: keeping Myc on a leash. Cell Cycle, 4(2), 249-52, 2005.
- 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 , 85301-5315, 2004.
- Qi, Ying, Gregory, Mark A, Li, Zhaoliang, Brousal, Jeffrey P, West, Kimberly, Hann, Stephen R p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature, 431(7009), 712-7, 2004.
- Gregory, Mark A, Qi, Ying, Hann, Stephen R Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem, 278(51), 51606-12, 2003.
- Cornwall, G A, Collis, R, Xiao, Q, Hsia, N, Hann, S R, B-Myc, a proximal caput epididymal protein, is dependent on androgens and testicular factors for expression.. Biol Reprod, 641600-7, 2001.
- Claassen, G F, Hann, S R, 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, 979498-503, 2000.
- Gregory, M A, Xiao, Q, Cornwall, G A, Lutterbach, B, Hann, S R, B-Myc is preferentially expressed in hormonally-controlled tissues and inhibits cellular proliferation.. Oncogene, 194886-95, 2000.
- Niklinski, J, Claassen, G, Meyers, C, Gregory, M A, Allegra, C J, Kaye, F J, Hann, S R, 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, 205276-84, 2000.
- Chang, D W, Claassen, G F, Hann, S R, Cole, M D, The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals.. Mol Cell Biol, 204309-19, 2000.
- Gregory, M A, Hann, S R c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol Cell Biol, 20(7), 2423-35, 2000.
- Claassen, G F, Hann, S R Myc-mediated transformation: the repression connection. Oncogene, 18(19), 2925-33, 1999.
- 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, 181219-1226, 1999.
- Lutterbach, B, Hann, S R c-Myc transactivation domain-associated kinases: questionable role for map kinases in c-Myc phosphorylation. J Cell Biochem, 72(4), 483-91, 1999.
- Xiao, Q, Claassen, G, Shi, J, Adachi, S, Sedivy, J, Hann, S R Transactivation-defective c-MycS retains the ability to regulate proliferation and apoptosis. Genes Dev, 12(24), 3803-8, 1998.
- Spotts, G D, Patel, S V, Xiao, Q, Hann, S R Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins. Mol Cell Biol, 17(3), 1459-68, 1997.
- Lutterbach, B, Hann, S R Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation. Oncogene, 14(8), 967-75, 1997.
- 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., 154031-4042, 1995.
- Hann, S R Methionine deprivation regulates the translation of functionally-distinct c-Myc proteins. Adv Exp Med Biol, 375107-16, 1995.
- Cornwall, G.A. and Hann, S.R "Specialized gene expression in the epididymis." Journal of Andrology, 16379-383, 1995.
- Cornwall, G.A. and Hann, S. R "Transient appearance of the CRES protein during spermatogenesis and caput epididymal sperm maturation." Mol. Reprod. and Develop., 4137-46, 1995.
- 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., 156702-6709, 1995.
- Lutterbach, B, Hann, S R Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis. Mol Cell Biol, 14(8), 5510-22, 1994.
- Hann, S R Regulation and function of non-AUG-initiated proto-oncogenes. Biochimie, 76(9), 880-6, 1994.
- Hann, S.R "Regulation and function of non-AUG-initiated proto-oncogenes." Biochiinie, 76880-886, 1994.
- Hann, S R, Dixit, M, Sears, R C, Sealy, L The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site. Genes Dev, 8(20), 2441-52, 1994.
- 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, 7671-682, 1993.
- Cornwall, G A, Orgebin-Crist, M C, Hann, S R Differential expression of the mouse mitochondrial genes and the mitochondrial RNA-processing endoribonuclease RNA by androgens. Mol Endocrinol, 6(7), 1032-42, 1992.
- Cornwall, G A, Orgebin-Crist, M C, Hann, S R 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, 47(4), 665-75, 1992.
- Cornwall, G A, Orgebin-Crist, M C, Hann, S R 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, 6(10), 1653-64, 1992.
- Hann, S R, Sloan-Brown, K, Spotts, G D Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation. Genes Dev, 6(7), 1229-40, 1992.
- Robinson-Benion, C, Salhany, K E, Hann, S R, Holt, J T Antisense inhibition of c-myc expression reveals common and distinct mechanisms of growth inhibition by TGF beta and TNF alpha. J Cell Biochem, 45(2), 188-95, 1991.
- Spotts, G D, Hann, S R Enhanced translation and increased turnover of c-myc proteins occur during differentiation of murine erythroleukemia cells. Mol Cell Biol, 10(8), 3952-64, 1990.
- 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, 1215-226, 1990.
- 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, 52185-195, 1988.
- 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, 314366-369, 1985.
- 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., 5114-126, 1985.
- Hann, S.R., Eisemnan, R.N "Proteins encoded by the human c-myc oncogene: Differential expression in neoplastic cells." Mol Cell Biol, 42486-2497, 1984.
- 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, 34789-798, 1983.