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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 
William P.  Tansey

William P. Tansey, Ph.D.

Co-Leader, Genome Maintenance Research Program
Ingram Professor of Cancer Research
Professor of Cell and Developmental Biology
Researcher

Contact Information:

Vanderbilt University Medical Center
4140-A MRB 3, 465 21st Ave So.
Nashville, TN 37232-8240
615-322-1993
Fax: 615-936-5673

Research Description

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.

Publications
  • 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 [print-electronic]. 2011 Aug 8/1/2011; 22(15): 2741-53. PMID: 21680712, PMCID: PMC3145549, PII: mbc.E11-05-0426, DOI: 10.1091/mbc.E11-05-0426, ISSN: 1939-4586.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21680712.
  • Lee SB, Kim JJ, Chung JS, Lee MS, Lee KH, Kim BS, Do Yoo Y. Romo1 is a negative-feedback regulator of Myc. J. Cell. Sci [print-electronic]. 2011 Jun 6/1/2011; 124(Pt 11): 1911-24. PMID: 21558421, PII: jcs.079996, DOI: 10.1242/jcs.079996, ISSN: 1477-9137.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21558421.
  • Simpson DR, Yu M, Zheng S, Zhao Z, Muthuswamy SK, Tansey WP. Epithelial cell organization suppresses Myc function by attenuating Myc expression. Cancer Res [print-electronic]. 2011 Jun 6/1/2011; 71(11): 3822-30. PMID: 21610111, PMCID: PMC3347713, PII: 0008-5472.CAN-10-3782, DOI: 10.1158/0008-5472.CAN-10-3782, ISSN: 1538-7445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21610111.
  • Thomas LR, Tansey WP. Proteolytic control of the oncoprotein transcription factor Myc. Adv. Cancer Res. 2011; 110: 77-106. PMID: 21704229, PII: B978-0-12-386469-7.00004-9, DOI: 10.1016/B978-0-12-386469-7.00004-9, ISSN: 0065-230X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21704229.
  • 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. 2011; 4: 62. PMID: 21824427, PMCID: PMC3212927, PII: 1755-8794-4-62, DOI: 10.1186/1755-8794-4-62, ISSN: 1755-8794.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21824427.
  • Collins GA, Gomez TA, Deshaies RJ, Tansey WP. Combined chemical and genetic approach to inhibit proteolysis by the proteasome. Yeast. 2010 Nov; 27(11): 965-74. PMID: 20625982, PMCID: PMC3566228, DOI: 10.1002/yea.1805, ISSN: 1097-0061.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20625982.
  • Wang X, Muratani M, Tansey WP, Ptashne M. Proteolytic instability and the action of nonclassical transcriptional activators. Curr. Biol [print-electronic]. 2010 May 5/11/2010; 20(9): 868-71. PMID: 20417106, PMCID: PMC3033761, PII: S0960-9822(10)00354-4, DOI: 10.1016/j.cub.2010.03.029, ISSN: 1879-0445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20417106.
  • Collins GA, Lipford JR, Deshaies RJ, Tansey WP. Gal4 turnover and transcription activation. Nature. 2009 Oct 10/8/2009; 461(7265): E7; discussion E8. PMID: 19812621, PMCID: PMC3072683, PII: nature08406, DOI: 10.1038/nature08406, ISSN: 1476-4687.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19812621.
  • Chakraborty AA, Tansey WP. Inference of cell cycle-dependent proteolysis by laser scanning cytometry. Exp. Cell Res [print-electronic]. 2009 Jun 6/10/2009; 315(10): 1772-8. PMID: 19331831, PMCID: PMC2680938, PII: S0014-4827(09)00035-4, DOI: 10.1016/j.yexcr.2009.01.011, ISSN: 1090-2422.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19331831.
  • Daulny A, Tansey WP. Damage control: DNA repair, transcription, and the ubiquitin-proteasome system. DNA Repair (Amst.) [print-electronic]. 2009 Apr 4/5/2009; 8(4): 444-8. PMID: 19272841, PII: S1568-7864(09)00009-3, DOI: 10.1016/j.dnarep.2009.01.017, ISSN: 1568-7864.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19272841.
  • Chakraborty AA, Tansey WP. Adenoviral E1A function through Myc. Cancer Res. 2009 Jan 1/1/2009; 69(1): 6-9. PMID: 19117980, PII: 69/1/6, DOI: 10.1158/0008-5472.CAN-08-3026, ISSN: 1538-7445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19117980.
  • 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 [print-electronic]. 2008 Dec 12/16/2008; 105(50): 19649-54. PMID: 19064926, PMCID: PMC2604917, PII: 0809372105, DOI: 10.1073/pnas.0809372105, ISSN: 1091-6490.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19064926.
  • Geng F, Tansey WP. Polyubiquitylation of histone H2B. Mol. Biol. Cell [print-electronic]. 2008 Sep; 19(9): 3616-24. PMID: 18562693, PMCID: PMC2526708, PII: E08-01-0050, DOI: 10.1091/mbc.E08-01-0050, ISSN: 1939-4586.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18562693.
  • Kurland JF, Tansey WP. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 2008 May 5/15/2008; 68(10): 3624-9. PMID: 18483244, PII: 68/10/3624, DOI: 10.1158/0008-5472.CAN-07-6552, ISSN: 1538-7445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18483244.
  • 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 [print-electronic]. 2008 Apr 4/22/2008; 105(16): 6103-8. PMID: 18413597, PMCID: PMC2329713, PII: 0802095105, DOI: 10.1073/pnas.0802095105, ISSN: 1091-6490.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18413597.
  • Leung A, Geng F, Daulny A, Collins G, Guzzardo P, Tansey WP. Transcriptional control and the ubiquitin-proteasome system. Ernst Schering Found Symp Proc. 2008; (1): 75-97. PMID: 19198065.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19198065.
  • Pal B, Chan NC, Helfenbaum L, Tan K, Tansey WP, Gething MJ. SCFCdc4-mediated degradation of the Hac1p transcription factor regulates the unfolded protein response in Saccharomyces cerevisiae. Mol. Biol. Cell [print-electronic]. 2007 Feb; 18(2): 426-40. PMID: 17108329, PMCID: PMC1783797, PII: E06-04-0304, DOI: 10.1091/mbc.E06-04-0304, ISSN: 1059-1524.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17108329.
  • Tansey WP. Denaturing protein immunoprecipitation from yeast. CSH Protoc. 2007; 2007: pdb.prot4643. PMID: 21356925.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21356925.
  • Tansey WP. Nondenaturing protein immunoprecipitation from Mammalian cells. CSH Protoc. 2007; 2007: pdb.prot4620. PMID: 21356922.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21356922.
  • Tansey WP. Pulse-chase assay for measuring protein stability in yeast. CSH Protoc. 2007; 2007: pdb.prot4641. PMID: 21356923.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21356923.
  • Tansey WP. Yeast Chromatin Immunoprecipitation (ChIP) Assay. CSH Protoc. 2007; 2007: pdb.prot4642. PMID: 21356924.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21356924.
  • Collins GA, Tansey WP. The proteasome: a utility tool for transcription?. Curr. Opin. Genet. Dev [print-electronic]. 2006 Apr; 16(2): 197-202. PMID: 16503126, PII: S0959-437X(06)00031-1, DOI: 10.1016/j.gde.2006.02.009, ISSN: 0959-437X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16503126.
  • Ezhkova E, Tansey WP. Chromatin immunoprecipitation to study protein-DNA interactions in budding yeast. Methods Mol. Biol. 2006; 313: 225-44. PMID: 16118437, PII: 1-59259-958-3:225, DOI: 10.1385/1-59259-958-3:225, ISSN: 1064-3745.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16118437.
  • 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. 2005 Nov 11/4/2005; 123(3): 423-36. PMID: 16269334, PII: S0092-8674(05)00819-6, DOI: 10.1016/j.cell.2005.08.015, ISSN: 0092-8674.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16269334.
  • 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. 2005 Aug 8/11/2005; 436(7052): 807-11. PMID: 16094360, PMCID: PMC4599579, PII: nature03845, DOI: 10.1038/nature03845, ISSN: 1476-4687.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16094360.
  • 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. 2005 Mar 3/25/2005; 120(6): 887-99. PMID: 15797387, PII: S0092-8674(04)01250-4, DOI: 10.1016/j.cell.2004.12.025, ISSN: 0092-8674.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15797387.
  • 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. 2005 Feb; 6(2): 177-83. PMID: 15678160, PMCID: PMC1299243, PII: 7400333, DOI: 10.1038/sj.embor.7400333, ISSN: 1469-221X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15678160.
  • Tansey WP. Death, destruction, and the proteasome. N. Engl. J. Med. 2004 Jul 7/22/2004; 351(4): 393-4. PMID: 15269322, PII: 351/4/393, DOI: 10.1056/NEJMcibr041505, ISSN: 1533-4406.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15269322.
  • Herbst A, Salghetti SE, Kim SY, Tansey WP. Multiple cell-type-specific elements regulate Myc protein stability. Oncogene. 2004 May 5/6/2004; 23(21): 3863-71. PMID: 15021906, PII: 1207492, DOI: 10.1038/sj.onc.1207492, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15021906.
  • Kurland JF, Tansey WP. Crashing waves of destruction: the cell cycle and APC(Cdh1) regulation of SCF(Skp2) [editorial]. Cancer Cell. 2004 Apr; 5(4): 305-6. PMID: 15093536, PII: S1535610804000911, ISSN: 1535-6108.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15093536.
  • Tubon TC, Tansey WP, Herr W. A nonconserved surface of the TFIIB zinc ribbon domain plays a direct role in RNA polymerase II recruitment. Mol. Cell. Biol. 2004 Apr; 24(7): 2863-74. PMID: 15024075, PMCID: PMC371104, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15024075.
  • Janicki SM, Tsukamoto T, Salghetti SE, Tansey WP, Sachidanandam R, Prasanth KV, Ried T, Shav-Tal Y, Bertrand E, Singer RH, Spector DL. From silencing to gene expression: real-time analysis in single cells. Cell. 2004 Mar 3/5/2004; 116(5): 683-98. PMID: 15006351, PII: S0092867404001710, ISSN: 0092-8674.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15006351.
  • Ezhkova E, Tansey WP. Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3. Mol. Cell. 2004 Feb 2/13/2004; 13(3): 435-42. PMID: 14967150, PII: S1097276504000267, ISSN: 1097-2765.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/14967150.
  • Kim SY, Herbst A, Tworkowski KA, Salghetti SE, Tansey WP. Skp2 regulates Myc protein stability and activity. Mol. Cell. 2003 May; 11(5): 1177-88. PMID: 12769843, PII: S1097276503001734, ISSN: 1097-2765.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12769843.
  • Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat. Rev. Mol. Cell Biol. 2003 Mar; 4(3): 192-201. PMID: 12612638, PII: nrm1049, DOI: 10.1038/nrm1049, ISSN: 1471-0072.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12612638.
  • Tworkowski KA, Salghetti SE, Tansey WP. Stable and unstable pools of Myc protein exist in human cells. Oncogene. 2002 Dec 12/5/2002; 21(55): 8515-20. PMID: 12466972, DOI: 10.1038/sj.onc.1205976, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12466972.
  • Alarcon-Vargas D, Tansey WP, Ronai Z. Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127-189 of c-myc. Oncogene. 2002 Jun 6/27/2002; 21(28): 4384-91. PMID: 12080469, DOI: 10.1038/sj.onc.1205543, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12080469.
  • Ejkova E, Tansey WP. Old dogs and new tricks: meeting on mechanisms of eukaryotic transcription. EMBO Rep. 2002 Mar; 3(3): 219-23. PMID: 11882540, PMCID: PMC1084018, PII: 3/3/219, DOI: 10.1093/embo-reports/kvf054, ISSN: 1469-221X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11882540.
  • Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B. Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol. Cell. 2002 Mar; 9(3): 481-91. PMID: 11931757, PII: S1097276502004677, ISSN: 1097-2765.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11931757.
  • Salghetti SE, Caudy AA, Chenoweth JG, Tansey WP. Regulation of transcriptional activation domain function by ubiquitin. Science [print-electronic]. 2001 Aug 8/31/2001; 293(5535): 1651-3. PMID: 11463878, PII: 1062079, DOI: 10.1126/science.1062079, ISSN: 0036-8075.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11463878.
  • Tansey WP. Transcriptional activation: risky business. Genes Dev. 2001 May 5/1/2001; 15(9): 1045-50. PMID: 11331599, DOI: 10.1101/gad.896501, ISSN: 0890-9369.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11331599.
  • Tansey WP. Transcriptional regulation: RUPture in the ER. Nature cell biology. 2000 Oct; 2(10) Sect. E175-7.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11025674.
  • 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. 2000 Mar 3/28/2000; 97(7): 3118-23. PMID: 10706616, PMCID: PMC16202, PII: 050007597, DOI: 10.1073/pnas.050007597, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10706616.
  • Herbst A, Tansey WP. HAM: a new epitope-tag for in vivo protein labeling. Mol. Biol. Rep. 2000; 27(4): 203-8. PMID: 11455955, ISSN: 0301-4851.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11455955.
  • Tansey WP. How cells use proteolysis to control their growth. Mol. Med. 1999 Dec; 5(12): 773-82. PMID: 10666476, PMCID: PMC2230494, PII: 0209, ISSN: 1076-1551.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10666476.
  • Salghetti SE, Kim SY, Tansey WP. Destruction of Myc by ubiquitin-mediated proteolysis: cancer-associated and transforming mutations stabilize Myc. EMBO J. 1999 Feb 2/1/1999; 18(3): 717-26. PMID: 9927431, PMCID: PMC1171164, DOI: 10.1093/emboj/18.3.717, ISSN: 0261-4189.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9927431.
  • Tansey WP, Herr W. TAFs: guilt by association?. Cell. 1997 Mar 3/21/1997; 88(6): 729-32. PMID: 9118213, PII: S0092-8674(00)81916-9, ISSN: 0092-8674.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9118213.
  • Tansey WP, Herr W. Selective use of TBP and TFIIB revealed by a TATA-TBP-TFIIB array with altered specificity. Science. 1997 Feb 2/7/1997; 275(5301): 829-31. PMID: 9012349, ISSN: 0036-8075.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9012349.
  • Pendergrast PS, Morrison D, Tansey WP, Hernandez N. Mutations in the carboxy-terminal domain of TBP affect the synthesis of human immunodeficiency virus type 1 full-length and short transcripts similarly. J. Virol. 1996 Aug; 70(8): 5025-34. PMID: 8764009, PMCID: PMC190456, ISSN: 0022-538X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8764009.
  • Tansey WP, Herr W. The ability to associate with activation domains in vitro is not required for the TATA box-binding protein to support activated transcription in vivo. Proc. Natl. Acad. Sci. U.S.A. 1995 Nov 11/7/1995; 92(23): 10550-4. PMID: 7479838, PMCID: PMC40649, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7479838.
  • Tansey WP, Ruppert S, Tjian R, Herr W. Multiple regions of TBP participate in the response to transcriptional activators in vivo. Genes Dev. 1994 Nov 11/15/1994; 8(22): 2756-69. PMID: 7958931, ISSN: 0890-9369.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7958931.
  • Gilbert MT, Sun J, Yan Y, Oddoux C, Lazarus A, Tansey WP, Lavin TN, Catanzaro DF. Renin gene promoter activity in GC cells is regulated by cAMP and thyroid hormone through Pit-1-dependent mechanisms. J. Biol. Chem. 1994 Nov 11/11/1994; 269(45): 28049-54. PMID: 7961740, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7961740.
  • Tansey WP, Schaufele F, Heslewood M, Handford C, Reudelhuber TL, Catanzaro DF. Distance-dependent interactions between basal, cyclic AMP, and thyroid hormone response elements in the rat growth hormone promoter. J. Biol. Chem. 1993 Jul 7/15/1993; 268(20): 14906-11. PMID: 8392063, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8392063.
  • Henderson BR, Tansey WP, Phillips SM, Ramshaw IA, Kefford RF. Transcriptional and posttranscriptional activation of urokinase plasminogen activator gene expression in metastatic tumor cells. Cancer Res. 1992 May 5/1/1992; 52(9): 2489-96. PMID: 1568219, ISSN: 0008-5472.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1568219.
  • Tansey WP, Catanzaro DF. Sp1 and thyroid hormone receptor differentially activate expression of human growth hormone and chorionic somatomammotropin genes. J. Biol. Chem. 1991 May 5/25/1991; 266(15): 9805-13. PMID: 2033067, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2033067.