University of Pittsburgh Department of Cell Biology
  • Research

    Posttranslational modifications such as ubiquitination, methylation, ADP-ribosylation as well as phosphorylation orchestrate genome stability, cell division, hormone-initiated signal transduction, apoptosis and tumorigenesis. Posttranslational modifications act as critical molecular switches or fine-tune operators that determine the activation, deactivation or subcellular localization of functional proteins. Emerging evidence has drawn attention to the modulation of regulatory proteins in response to extrinsic/intrinsic signaling being executed simultaneously by multiple posttranslational modifications. Research interests in my laboratory seek to address how defects in the ubiquitin-proteasome system (E3 ligase/deubiquitinase), protein methyltransferase and poly (ADP-ribose) polymerase 1 (PARP1) would result in genomic instability, abnormal cell cycle or apoptosis, and aberrant signal transductions (e.g., ER, TGF-β, EGFR and Hippo) that predispose otherwise normal cells to become cancerous tumor cells. The ultimate objective is to integrate our basic research with clinical translational studies that would allow the development of new anti-cancer therapy thereby fully exploiting our knowledge of posttranslational modifications. To achieve our goals, we have developed a multidisciplinary approach that includes biochemical, cell biological, genetic, protein structural analyses as well as the use of animal models and analyses of clinical specimens.

  • Publications

    (In press)

    1. He M., Zhou Z., Wu G., Chen Q. and Wan Y. 2017. Ubiquitinase protein ligase and deubiquitinase in tumor metastasis and therapeutics. Pharmacology & Therapeutics (in press)
    2. Zhihua Liu, Honghong Zhou, Yong-Shuo Liu, Rui Zhu, Fang Ding, Yong Wan, and Yi Li. 2017. FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation. Oncogene (in press)
    3. Zhou Z, Shrivastava I, Lou A, He M, Huang Y, Liu Z, Bahar I and Wan Y. 2017. Novel insight into USP11-XIAP axis in malignant tumor transformation. EBioMedicine (in press).
    4. He M, Zhou Z, Shah AA, Tao J, Zou H, Chen Q, and Wan Y. 2016. The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics. Cell and Bioscience. (in press)
    1. He M, Zhou Z, Wu G, Chen Q, Wan Y. Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication.. Pharmacol Ther. 2017 Mar 6;():. pii: S0163-7258(17)30081-5. doi: 10.1016/j.pharmthera.2017.03.001. PubMed PMID: 28279784;
    2. Zhou Z, Luo A, Shrivastava I, He M, Huang Y, Bahar I, Liu Z, Wan Y. Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis.. EBioMedicine. 2017 Feb;15():48-61. doi: 10.1016/j.ebiom.2016.12.014. PubMed PMID: 28040451;
    3. Lu S, Cai C, Yan G, Zhou Z, Wan Y, Cooper GF, Obeid LM, Hannun YA, Lee AV, Lu X. Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations. Cancer Res. 2016 Oct 10. PMID: 27758891 [Epub ahead of print]
    4. Zhou Z, He M, Shah AA, Wan Y. Insights into APC/C: from cellular function to diseases and therapeutics. Cell Div. 2016 Jul 13;11:9. doi: 10.1186/s13008-016-0021-6. eCollection 2016. Review. [link]
    5. He M, Zhou Z, Shah AA, Hong Y, Chen Q, Wan Y. New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics. Cell Div. 2016 Mar 31;11:4. doi: 10.1186/s13008-016-0013-6. eCollection 2016. Review. [link]
    6. Hu D, Gur M, Zhou Z, Gamper A, Hung MC, Fujita N, Lan L, Bahar I, Wan Y. Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis. Nat Commun. 2015 Sep 30;6:8419. doi: 10.1038/ncomms9419. [link]
    7. He H, Li S, Hong Y, Zou H, Chen H, Ding F, Wan Y, Liu Z. Krüppel-like Factor 4 Promotes Esophageal Squamous Cell Carcinoma Differentiation by Up-regulating Keratin 13 Expression. J Biol Chem. 2015 May 22;290(21):13567-77. doi: 10.1074/jbc.M114.629717. Epub 2015 Apr 7. [link]
    8. Zhou Z, Jing C, Zhang L, Takeo F, Kim H, Huang Y, Liu Z, Wan Y. Regulation of Rad17 protein turnover unveils an impact of Rad17-APC cascade in breast carcinogenesis and treatment. J Biol Chem. 2013 Jun 21;288(25):18134-45. doi: 10.1074/jbc.M113.456962. Epub 2013 May 1. [link]
    9. Vasilatos SN, Katz TA, Oesterreich S, Wan Y, Davidson NE, Huang Y. Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis. 2013 Jun;34(6):1196-207. doi: 10.1093/carcin/bgt033. Epub 2013 Jan 25. [link]
    10. Hu D, Zhou Z, Davidson NE, Huang Y, Wan Y. Novel insight into KLF4 proteolytic regulation in estrogen receptor signaling and breast carcinogenesis. J Biol Chem. 2012 Apr 20;287(17):13584-97. doi: 10.1074/jbc.M112.343566. Epub 2012 Mar 2. [link]
    11. Gamper AM, Qiao X, Kim J, Zhang L, DeSimone MC, Rathmell WK, Wan Y. Regulation of KLF4 turnover reveals an unexpected tissue-specific role of pVHL in tumorigenesis. Mol Cell. 2012 Jan 27;45(2):233-43. doi: 10.1016/j.molcel.2011.11.031. Erratum in: Mol Cell. 2015 Oct 15;60(2):339. [link]
    12. Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O, Hu D, Wan Y, Seng V, Sheppard-Tillman H, Martin P, Kelly K. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol. 2012 Mar;32(5):941-53. doi: 10.1128/MCB.06306-11. Epub 2011 Dec 27. [link]
    13. Hu D, Qiao X, Wu G, Wan Y. The emerging role of APC/CCdh1 in development. Semin Cell Dev Biol. 2011 Aug;22(6):579-85. doi: 10.1016/j.semcdb.2011.03.012. Epub 2011 Apr 7. Review. [link]
    14. Liu W, Zong W, Wu G, Fujita T, Li W, Wu J, Wan Y. Turnover of BRCA1 involves in radiation-induced apoptosis. PLoS One. 2010 Dec 31;5(12):e14484. doi: 10.1371/journal.pone.0014484. [link]
    15. Hu D, Liu W, Wu G, Wan Y. Nuclear translocation of Skp2 facilitates its destruction in response to TGFβ signaling. Cell Cycle. 2011 Jan 15;10(2):285-92. Epub 2011 Jan 15. [link]
    16. Zhang L, Fujita T, Wu G, Xiao X, Wan Y. Phosphorylation of the anaphase-promoting complex/Cdc27 is involved in TGF-beta signaling. J Biol Chem. 2011 Mar 25;286(12):10041-50. doi: 10.1074/jbc.M110.205518. Epub 2011 Jan 5. [link]
    17. Hu D, Wan Y. Regulation of Krüppel-like factor 4 by the anaphase promoting complex pathway is involved in TGF-beta signaling. J Biol Chem. 2011 Mar 4;286(9):6890-901. doi: 10.1074/jbc.M110.179952. Epub 2010 Dec 22. [link]
    18. Qiao X, Zhang L, Gamper AM, Fujita T, Wan Y. APC/C-Cdh1: from cell cycle to cellular differentiation and genomic integrity. Cell Cycle. 2010 Oct 1;9(19):3904-12. Epub 2010 Oct 11. Review. [link]
    19. Zhang L, Park CH, Wu J, Kim H, Liu W, Fujita T, Balasubramani M, Schreiber EM, Wang XF, Wan Y. Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress. EMBO J. 2010 May 19;29(10):1726-37. doi: 10.1038/emboj.2010.55. Epub 2010 Apr 27. [link]
    20. Fujita T, Liu W, Doihara H, Wan Y. An in vivo study of Cdh1/APC in breast cancer formation. Int J Cancer. 2009 Aug 15;125(4):826-36. doi: 10.1002/ijc.24399. [link]
    21. Fujita T, Epperly MW, Zou H, Greenberger JS, Wan Y. Regulation of the anaphase-promoting complex-separase cascade by transforming growth factor-beta modulates mitotic progression in bone marrow stromal cells. Mol Biol Cell. 2008 Dec;19(12):5446-55. doi: 10.1091/mbc.E08-03-0289. Epub 2008 Oct 8. [link]
    22. Fujita T, Liu W, Doihara H, Wan Y. Regulation of Skp2-p27 axis by the Cdh1/anaphase-promoting complex pathway in colorectal tumorigenesis. Am J Pathol. 2008 Jul;173(1):217-28. doi: 10.2353/ajpath.2008.070957. Epub 2008 Jun 5. PubMed PMID: 18535175; PubMed Central PMCID: PMC2438299.
    23. Fujita T, Liu W, Doihara H, Date H, Wan Y. Dissection of the APCCdh1-Skp2 cascade in breast cancer. Clin Cancer Res. 2008 Apr 1;14(7):1966-75. doi: 10.1158/1078-0432.CCR-07-1585. [link]
    24. Liu W, Li W, Fujita T, Yang Q, Wan Y. Proteolysis of CDH1 enhances susceptibility to UV radiation-induced apoptosis. Carcinogenesis. 2008 Feb;29(2):263-72. doi: 10.1093/carcin/bgm251. Epub 2008 Jan 3. [link]
    25. Li W, Wu G, Wan Y. The dual effects of Cdh1/APC in myogenesis. FASEB J. 2007 Nov;21(13):3606-17. Epub 2007 Jun 29. [link]
    26. Liu W, Wu G, Li W, Lobur D, Wan Y. Cdh1-anaphase-promoting complex targets Skp2 for destruction in transforming growth factor beta-induced growth inhibition. Mol Cell Biol. 2007 Apr;27(8):2967-79. Epub 2007 Feb 5. [link]
    27. Wu G, Glickstein S, Liu W, Fujita T, Li W, Yang Q, Duvoisin R, Wan Y. The anaphase-promoting complex coordinates initiation of lens differentiation. Mol Biol Cell. 2007 Mar;18(3):1018-29. Epub 2007 Jan 10. [link]
    28. Macdonald M, Wan Y, Wang W, Roberts E, Cheung TH, Erickson R, Knuesel MT, Liu X. Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34. Oncogene. 2004 Jul 22;23(33):5643-53. [link]
    29. Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature. 2004 Mar 11;428(6979):194-8. [link]
    30. Knuesel M, Wan Y, Xiao Z, Holinger E, Lowe N, Wang W, Liu X. Identification of novel protein-protein interactions using a versatile mammalian tandem affinity purification expression system. Mol Cell Proteomics. 2003 Nov;2(11):1225-33. Epub 2003 Sep 8. [link]
    31. Wan Y, Liu X, Kirschner MW. The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Mol Cell. 2001 Nov;8(5):1027-39. [link]
    32. Wan Y, Kirschner MW. Identification of multiple CDH1 homologues in vertebrates conferring different substrate specificities. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13066-71. Epub 2001 Oct 30. [link]
    33. Jiang Y, Ma W, Wan Y, Kozasa T, Hattori S, Huang XY. The G protein G alpha12 stimulates Bruton\'s tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature. 1998 Oct 22;395(6704):808-13. [link]
    34. Wan Y, Huang XY. Analysis of the Gs/mitogen-activated protein kinase pathway in mutant S49 cells. J Biol Chem. 1998 Jun 5;273(23):14533-7. [link]
    35. Wan Y, Bence K, Hata A, Kurosaki T, Veillette A, Huang XY. Genetic evidence for a tyrosine kinase cascade preceding the mitogen-activated protein kinase cascade in vertebrate G protein signaling. J Biol Chem. 1997 Jul 4;272(27):17209-15. [link]
    36. Wan Y, Kurosaki T, Huang XY. Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Nature. 1996 Apr 11;380(6574):541-4. [link]
    37. Langhans-Rajasekaran SA, Wan Y, Huang XY. Activation of Tsk and Btk tyrosine kinases by G protein beta gamma subunits. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8601-5. [link]


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