William P. Tansey, Ph.D.
Co-Leader, Genome Maintenance Research Program
Ingram Professor of Cancer Research
Professor of Cell and Developmental Biology
Vanderbilt University Medical Center
4140-A MRB 3, 465 21st Ave So.
Nashville, TN 37232-8240
Oncoproteins, Ubiquitin, Proteolysis
Transcription and ubiquitin-mediated proteolysis are two processes that might seem to have little in common. Transcription is the first step in the life of any protein; proteolysis the last. Despite the disparate nature of these processes, a growing body of evidence suggests that components of the ubiquitin-proteasome system are intimately involved in the regulation of gene expression. Research in my laboratory is geared toward understanding how these two processes intersect, and the consequences of this intersection for cellular growth control.
Our current research is divided into two areas. One area is focused on revealing the basic mechanisms that connect the transcription and ubiquitin systems. We have previously found that the destruction of transcription factors is intimately tied to their ability to activate transcription, and that components of the proteasome play an essential role in the regulation of histone modifications. We are currently studying how prototypical transcription factors, such as the yeast activator Gal4, interact with ubiquitin and with the proteasome to regulate gene expression.
Our second area of research is focused on understanding how the destruction of transcription factors impacts mammalian cell growth control. These studies center on Myc, an oncoprotein transcription factor that features prominently in human cancer. We have previously found that Myc is rapidly destroyed by the ubiquitin-system, and that oncogenic mutations within Myc stabilize the protein, allowing it to accumulate. We seek to identify the cellular machinery that targets Myc for ubiquitin-mediated destruction, and learn how the regulation of Myc turnover--and loss of control of this process--relates to human cancer.
- Simpson, DR, Yu, M, Zheng, S, Zhao, Z, Muthuswamy, SK, Tansey, WP Epithelial cell organization suppresses Myc function by attenuating Myc expression. Cancer Res, 71(11), 3822-30, 2011.
- Leung, A, Cajigas, I, Jia, P, Ezhkova, E, Brickner, JH, Zhao, Z, Geng, F, Tansey, WP Histone H2B ubiquitylation and H3 lysine 4 methylation prevent ectopic silencing of euchromatic loci important for the cellular response to heat. Mol Biol Cell, 22(15), 2741-2753, 2011.
- Zheng, S, Tansey, WP, Hiebert, SW, Zhao, Z Integrative network analysis identifies key genes and pathways in the progression of hepatitis C virus induced hepatocellular carcinoma. BMC Med Genomics, 4(1), 62, 2011.
- Thomas, LR, Tansey, WP Proteolytic control of the oncoprotein transcription factor Myc. Adv Cancer Res, 11077-106, 2011.
- Lee, SB, Kim, JJ, Chung, JS, Lee, MS, Lee, KH, Kim, BS, Tansey, WP, Do Yoo, Y Romo1 is a negative-feedback regulator of Myc. J Cell Sci, 124(Pt 11), 1911-24, 2011.
- Collins, GA, Gomez, TA, Deshaies, RJ, Tansey, WP Combined chemical and genetic approach to inhibit proteolysis by the proteasome. Yeast, 27(11), 965-74, 2010.
- Wang, X, Muratani, M, Tansey, WP, Ptashne, M Proteolytic instability and the action of nonclassical transcriptional activators. Curr Biol, 20(9), 868-71, 2010.
- Chakraborty, AA, Tansey, WP Adenoviral E1A function through Myc. Cancer Res, 69(1), 6-9, 2009.
- Daulny, A, Tansey, WP Damage control: DNA repair, transcription, and the ubiquitin-proteasome system. DNA Repair (Amst), 8(4), 444-8, 2009.
- Collins, GA, Lipford, JR, Deshaies, RJ, Tansey, WP Gal4 turnover and transcription activation. Nature, 461(7265), E7; discussion E8, 2009.
- Chakraborty, AA, Tansey, WP Inference of cell cycle-dependent proteolysis by laser scanning cytometry. Exp Cell Res, 315(10), 1772-8, 2009.
- Tworkowski, KA, Chakraborty, AA, Samuelson, AV, Seger, YR, Narita, M, Hannon, GJ, Lowe, SW, Tansey, WP Adenovirus E1A targets p400 to induce the cellular oncoprotein Myc. Proc Natl Acad Sci U S A, 105(16), 6103-8, 2008.
- Daulny, A, Geng, F, Muratani, M, Geisinger, JM, Salghetti, SE, Tansey, WP Modulation of RNA polymerase II subunit composition by ubiquitylation. Proc Natl Acad Sci U S A, 105(50), 19649-54, 2008.
- Kurland, JF, Tansey, WP Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res, 68(10), 3624-9, 2008.
- Geng, F, Tansey, WP Polyubiquitylation of histone H2B. Mol Biol Cell, 19(9), 3616-24, 2008.
- Leung, A, Geng, F, Daulny, A, Collins, G, Guzzardo, P, Tansey, WP Transcriptional control and the ubiquitin-proteasome system. Ernst Schering Found Symp Proc, (1), 75-97, 2008.
- Tansey, WP Denaturing protein immunoprecipitation from yeast. CSH Protoc, 2007pdb.prot4643, 2007.
- Tansey, WP Nondenaturing protein immunoprecipitation from Mammalian cells. CSH Protoc, 2007pdb.prot4620, 2007.
- Tansey, WP Pulse-chase assay for measuring protein stability in yeast. CSH Protoc, 2007pdb.prot4641, 2007.
- Tansey, WP Yeast Chromatin Immunoprecipitation (ChIP) Assay. CSH Protoc, 2007pdb.prot4642, 2007.
- Ezhkova, E, Tansey, WP Chromatin immunoprecipitation to study protein-DNA interactions in budding yeast. Methods Mol Biol, 313225-44, 2006.
- Collins, GA, Tansey, WP The proteasome: a utility tool for transcription. Curr Opin Genet Dev, 16(2), 197-202, 2006.
- Herbst, A, Hemann, MT, Tworkowski, KA, Salghetti, SE, Lowe, SW, Tansey, WP A conserved element in Myc that negatively regulates its proapoptotic activity. EMBO Rep, 6(2), 177-83, 2005.
- Hemann, MT, Bric, A, Teruya-Feldstein, J, Herbst, A, Nilsson, JA, Cordon-Cardo, C, Cleveland, JL, Tansey, WP, Lowe, SW Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature, 436(7052), 807-11, 2005.
- Muratani, M, Kung, C, Shokat, KM, Tansey, WP The F box protein Dsg1/Mdm30 is a transcriptional coactivator that stimulates Gal4 turnover and cotranscriptional mRNA processing. Cell, 120(6), 887-99, 2005.
- Lee, D, Ezhkova, E, Li, B, Pattenden, SG, Tansey, WP, Workman, JL The proteasome regulatory particle alters the SAGA coactivator to enhance its interactions with transcriptional activators. Cell, 123(3), 423-36, 2005.
- Herbst, A, Salghetti, SE, Kim, SY, Tansey, WP Multiple cell-type-specific elements regulate Myc protein stability. Oncogene, 23(21), 3863-71, 2004.
- Ezhkova, E, Tansey, WP Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3. Mol Cell, 13(3), 435-42, 2004.
- Muratani, M, Tansey, WP How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol, 4(3), 192-201, 2003.
- Kim, SY, Herbst, A, Tworkowski, KA, Salghetti, SE, Tansey, WP Skp2 regulates Myc protein stability and activity. Mol Cell, 11(5), 1177-88, 2003.
- Tworkowski, KA, Salghetti, SE, Tansey, WP Stable and unstable pools of Myc protein exist in human cells. Oncogene, 21(55), 8515-20, 2002.
- Salghetti, SE, Caudy, AA, Chenoweth, JG, Tansey, WP Regulation of transcriptional activation domain function by ubiquitin. Science, 293(5535), 1651-3, 2001.
- Salghetti, SE, Muratani, M, Wijnen, H, Futcher, B, Tansey, WP Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis. Proc Natl Acad Sci U S A, 97(7), 3118-23, 2000.
- Salghetti, SE, Kim, SY, Tansey, WP Destruction of Myc by ubiquitin-mediated proteolysis: cancer-associated and transforming mutations stabilize Myc. EMBO J, 18(3), 717-26, 1999.