DF/HCC Program Affiliation

Cancer Cell Biology
Cancer Genetics

DF/HCC Associations

Director, Monoclonal Antibody
Member, Center Scientific Council

Research Abstract

This laboratory is focused on understanding the mechanisms of cellular transformation. In particular, we study how SV40 large T antigen (T Ag) is capable of inducing all of the cellular changes associated with oncogenic transformation. Cellular transformation by T Ag is dependent, at least in part, on inactivation of cellular tumor suppressers. Genetic analysis has led to identification of three transforming domains of T Ag: a C-terminal domain that binds the p53 tumor suppresser and the p300/CBP transcription coactivators; the LxCxE domain that binds the retinoblastoma (pRB) family of tumor suppressers, including pRB, p107 and p130 and an N-terminal domain that resembles the J domain found in the DnaJ/hsp40 family of molecular chaperones. The laboratory seeks to identify novel cellular targets of SV40 T Ag. We have identified a novel E3 ubiquitin ligase, CUL7/FBXW8, that binds to T Ag and appears to contribute to viral oncogenesis.

Publications

• Skaar JR, Florens L, Tsutsumi T, Arai T, Tron A, Swanson SK, Washburn MP, DeCaprio JA.PARC and CUL7 form atypical cullin RING ligase complexes.Cancer Res 2007 Mar 1;67(5):2006-14.
  17332328
• Poulin DL, DeCaprio JA.Is there a role for SV40 in human cancer?.J Clin Oncol 2006 Sep 10;24(26):4356-65.
  16963733
• Kasper JS, Arai T, Decaprio JA.A novel p53-binding domain in CUL7.Biochem Biophys Res Commun 2006 Jul 13.
  16875676
• Poulin DL, DeCaprio JA.The carboxyl-terminal domain of large T antigen rescues SV40 host range activity in trans independent of acetylation.Virology 2006 May 25;349(1):212-21.
  16510165
• Kasper JS, Kuwabara H, Arai T, Ali SH, DeCaprio JA.Simian virus 40 large T antigen's association with the CUL7 SCF complex contributes to cellular transformation.J Virol 2005 Sep;79(18):11685-92.
  16140746
• Skaar JR, Arai T, DeCaprio JA.Dimerization of CUL7 and PARC is not required for all CUL7 functions and mouse development.Mol Cell Biol 2005 Jul;25(13):5579-89.
  15964813
• Litovchick L, Chestukhin A, DeCaprio JA.Glycogen synthase kinase 3 phosphorylates RBL2/p130 during quiescence.Mol Cell Biol 2004 Oct;24(20):8970-80.
  15456871
• Buchmann AM, Skaar JR, DeCaprio JA.Activation of a DNA damage checkpoint response in a TAF1-defective cell line.Mol Cell Biol 2004 Jun;24(12):5332-9.
  15169897
• Arai T, Kasper JS, Skaar JR, Ali SH, Takahashi C, DeCaprio JA.Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis.Proc Natl Acad Sci U S A 2003 Aug 19;100(17):9855-60.
  12904573
• Borger DR, Gavrilescu LC, Bucur MC, Ivan M, Decaprio JA.AMP-activated protein kinase is essential for survival in chronic hypoxia.Biochem Biophys Res Commun 2008 May 30;370(2):230-4.
  18359290
• Tsutsumi T, Kuwabara H, Arai T, Xiao Y, Decaprio JA.Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice.Mol Cell Biol 2008 Jan;28(2):743-51.
  17998335
• Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, Bulmer SE, Decaprio JA, Hahn WC.The Tumor Suppressor PP2A Abeta Regulates the RalA GTPase.Cell 2007 Jun 1;129(5):969-982.
  17540176
• Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, Decaprio JA.Evolutionarily Conserved Multisubunit RBL2/p130 and E2F4 Protein Complex Represses Human Cell Cycle-Dependent Genes in Quiescence.Mol Cell 2007
  17531812
• Borger DR, DeCaprio JA.Targeting of p300/CREB binding protein coactivators by simian virus 40 is mediated through p53.J Virol 2006 May;80(9):4292-303.
  16611888
• Poulin DL, Kung AL, DeCaprio JA.p53 targets simian virus 40 large T antigen for acetylation by CBP.J Virol 2004 Aug;78(15):8245-53.
  15254196
• Dalal SN, Yaffe MB, DeCaprio JA.14-3-3 family members act coordinately to regulate mitotic progression.Cell Cycle 2004 May;3(5):672-7.
  15107609
• Ali SH, Kasper JS, Arai T, DeCaprio JA.Cul7/p185/p193 binding to simian virus 40 large T antigen has a role in cellular transformation.J Virol 2004 Mar;78(6):2749-57.
  14990695
• Qi H, Gervais ML, Li W, DeCaprio JA, Challis JR, Ohh M.Molecular cloning and characterization of the von Hippel-Lindau-like protein.Mol Cancer Res 2004 Jan;2(1):43-52.
  14757845
• Towbin H, Bair KW, DeCaprio JA, Eck MJ, Kim S, Kinder FR, Morollo A, Mueller DR, Schindler P, Song HK, van Oostrum J, Versace RW, Voshol H, Wood J, Zabludoff S, Phillips PE.Proteomics-based target identification: bengamides as a new class of methionine am
  14534293
• Lin JY, DeCaprio JA.SV40 large T antigen promotes dephosphorylation of p130.J Biol Chem 2003 Nov 21;278(47):46482-7.
  12968030
• Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC.Telomerase maintains telomere structure in normal human cells.Cell 2003 Jul 25;114(2):241-53.
  12887925
• Li D, Zhao R, Lilyestrom W, Gai D, Zhang R, DeCaprio JA, Fanning E, Jochimiak A, Szakonyi G, Chen XS.Structure of the replicative helicase of the oncoprotein SV40 large tumour antigen.Nature 2003 May 29;423(6939):512-8.
  12774115
• Sanhes L, Tang R, Delmer A, DeCaprio JA, Ajchenbaum-Cymbalista F.Fludarabine-induced apoptosis of B chronic lymphocytic leukemia cells includes early cleavage of p27kip1 by caspases.Leukemia 2003 Jun;17(6):1104-11.
  12764376
• Chestukhin A, Pfeffer C, Milligan S, DeCaprio JA, Pellman D.Processing, localization, and requirement of human separase for normal anaphase progression.Proc Natl Acad Sci U S A 2003 Apr 15;100(8):4574-9.
  12672959
• Chestukhin A, DeCaprio JA.Western blot screening for monoclonal antibodies against human separase.J Immunol Methods 2003 Mar 1;274(1-2):105-13.
  12609537
• Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ.NFATc2-mediated repression of cyclin-dependent kinase 4 expression.Mol Cell 2002 Nov;10(5):1071-81.
  12453415
• Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA.Enumeration of the simian virus 40 early region elements necessary for human cell transformation.Mol Cell Biol 2002 Apr;22(7):2111-23.
  11884599
• Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni JV, Dalal SN, DeCaprio JA, Greenberg ME, Yaffe MB.14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport.J Cell Biol 2002 Mar 4;156(5):817-28.
  11864996
• Ayté J, Schweitzer C, Zarzov P, Nurse P, DeCaprio JA.Feedback regulation of the MBF transcription factor by cyclin Cig2.Nat Cell Biol 2001 Dec;3(12):1043-50.
  11781565
• Chestukhin A, Litovchick L, Rudich K, DeCaprio JA.Nucleocytoplasmic shuttling of p130/RBL2: novel regulatory mechanism.Mol Cell Biol 2002 Jan;22(2):453-68.
  11756542
• Ali SH, DeCaprio JA.Cellular transformation by SV40 large T antigen: interaction with host proteins.Semin Cancer Biol 2001 Feb;11(1):15-23.
  11243895
• Hall C, Nelson DM, Ye X, Baker K, DeCaprio JA, Seeholzer S, Lipinski M, Adams PD.HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression.Mol Cell Biol 2001 Mar;21(5):1854-65.
  11238922
• Zalvide J, DeCaprio JA, Stubdal H.Binding of SV40 large T antigen to the retinoblastoma susceptibility gene product and related proteins.Methods Mol Biol 2001;165:213-8.
  11217388
• Miyake S, Sellers WR, Safran M, Li X, Zhao W, Grossman SR, Gan J, DeCaprio JA, Adams PD, Kaelin WG.Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle.Mol Cell Biol 2000 Dec;20(23):8889-902.
  11073989
• Canhoto AJ, Chestukhin A, Litovchick L, DeCaprio JA.Phosphorylation of the retinoblastoma-related protein p130 in growth-arrested cells.Oncogene 2000 Oct 19;19(44):5116-22.
  11042701
• Chao HH, Buchmann AM, DeCaprio JA.Loss of p19(ARF) eliminates the requirement for the pRB-binding motif in simian virus 40 large T antigen-mediated transformation.Mol Cell Biol 2000 Oct;20(20):7624-33.
  11003658
• Baksh S, DeCaprio JA, Burakoff SJ.Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4.Oncogene 2000 Jun 1;19(24):2820-7.
  10851085
• Vairo G, Soos TJ, Upton TM, Zalvide J, DeCaprio JA, Ewen ME, Koff A, Adams JM.Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation.Mol Cell Biol 2000 Jul;20(13):4745-53.
  10848600
• Gjoerup O, Chao H, DeCaprio JA, Roberts TM.pRB-dependent, J domain-independent function of simian virus 40 large T antigen in override of p53 growth suppression.J Virol 2000 Jan;74(2):864-74.
  10623749
• Dalal SN, Schweitzer CM, Gan J, DeCaprio JA.Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site.Mol Cell Biol 1999 Jun;19(6):4465-79.
  10330186
• Chauhan D, Hideshima T, Treon S, Teoh G, Raje N, Yoshihimito S, Tai YT, Li W, Fan J, DeCaprio J, Anderson KC.Functional interaction between retinoblastoma protein and stress-activated protein kinase in multiple myeloma cells.Cancer Res 1999 Mar 15;59(6):1
  10096546
• Shim WS, DiRenzo J, DeCaprio JA, Santen RJ, Brown M, Jeng MH.Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium.Proc Natl Acad Sci U S A 1999 Jan 5;96(1):208-13.
  9874797
• Marin MC, Jost CA, Irwin MS, DeCaprio JA, Caput D, Kaelin WG.Viral oncoproteins discriminate between p53 and the p53 homolog p73.Mol Cell Biol 1998 Nov;18(11):6316-24.
  9774648
• Maheswaran S, Englert C, Zheng G, Lee SB, Wong J, Harkin DP, Bean J, Ezzell R, Garvin AJ, McCluskey RT, DeCaprio JA, Haber DA.Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70.Ge
  9553041
• Zalvide J, Stubdal H, DeCaprio JA.The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins.Mol Cell Biol 1998 Mar;18(3):1408-15.
  9488456
• Sheng Q, Denis D, Ratnofsky M, Roberts TM, DeCaprio JA, Schaffhausen B.The DnaJ domain of polyomavirus large T antigen is required to regulate Rb family tumor suppressor function.J Virol 1997 Dec;71(12):9410-6.
  9371601
• Ayté J, Leis JF, DeCaprio JA.The fission yeast protein p73res2 is an essential component of the mitotic MBF complex and a master regulator of meiosis.Mol Cell Biol 1997 Nov;17(11):6246-54.
  9343385
• Stubdal H, Zalvide J, Campbell KS, Schweitzer C, Roberts TM, DeCaprio JA.Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen.Mol Cell Biol 1997 Sep;17(9):4979-90.
  9271376
• Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM.Binding and modulation of p53 by p300/CBP coactivators.Nature 1997 Jun 19;387(6635):823-7.
  9194565
• Campbell KS, Mullane KP, Aksoy IA, Stubdal H, Zalvide J, Pipas JM, Silver PA, Roberts TM, Schaffhausen BS, DeCaprio JA.DnaJ/hsp40 chaperone domain of SV40 large T antigen promotes efficient viral DNA replication.Genes Dev 1997 May 1;11(9):1098-110.
  9159391
• Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA, Ewen ME.Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein.Nature 1997 Mar 13;386(6621):177-81.
  9062190
• Stubdal H, Zalvide J, DeCaprio JA.Simian virus 40 large T antigen alters the phosphorylation state of the RB-related proteins p130 and p107.J Virol 1996 May;70(5):2781-8.
  8627752
• Zalvide J, DeCaprio JA.Role of pRb-related proteins in simian virus 40 large-T-antigen-mediated transformation.Mol Cell Biol 1995 Oct;15(10):5800-10.
  7565733
• Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG.Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C.Science 1995 Sep 8;269(5229):1444-6.
  7660130
• Ayté J, Leis JF, Herrera A, Tang E, Yang H, DeCaprio JA.The Schizosaccharomyces pombe MBF complex requires heterodimerization for entry into S phase.Mol Cell Biol 1995 May;15(5):2589-99.
  7739540
• Chittenden T, Livingston DM, DeCaprio JA.Cell cycle analysis of E2F in primary human T cells reveals novel E2F complexes and biochemically distinct forms of free E2F.Mol Cell Biol 1993 Jul;13(7):3975-83.
  8321204
• Kaelin WG, Krek W, Sellers WR, DeCaprio JA, Ajchenbaum F, Fuchs CS, Chittenden T, Li Y, Farnham PJ, Blanar MA.Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties.Cell 1992 Jul 24;70(2):351-64.
  1638635
• DeCaprio JA, Furukawa Y, Ajchenbaum F, Griffin JD, Livingston DM.The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression.Proc Natl Acad Sci U S A 1992 Mar 1;89(5):1795-8.
  1531876
• Ishida Y, Furukawa Y, Decaprio JA, Saito M, Griffin JD.Treatment of myeloid leukemic cells with the phosphatase inhibitor okadaic acid induces cell cycle arrest at either G1/S or G2/M depending on dose.J Cell Physiol 1992 Mar;150(3):484-92.
  1311329
• Shirodkar S, Ewen M, DeCaprio JA, Morgan J, Livingston DM, Chittenden T.The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner.Cell 1992 Jan 10;68(1):157-66.
  1531040
• DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG.Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial.J Clin Oncol 1991 Dec;9(12):2128-33.
  1960554
• Furukawa Y, DeCaprio JA, Belvin M, Griffin JD.Heterogeneous expression of the product of the retinoblastoma susceptibility gene in primary human leukemia cells.Oncogene 1991 Aug;6(8):1343-6.
  1886710
• Kaelin WG, Pallas DC, DeCaprio JA, Kaye FJ, Livingston DM.Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product.Cell 1991 Feb 8;64(3):521-32.
  1825028
• Laiho M, Rönnstrand L, Heino J, Decaprio JA, Ludlow JW, Livingston DM, Massagué J.Control of junB and extracellular matrix protein expression by transforming growth factor-beta 1 is independent of simian virus 40 T antigen-sensitive growth-sensitive growt
  1990295
• Laiho M, DeCaprio JA, Ludlow JW, Livingston DM, Massagué J.Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation.Cell 1990 Jul 13;62(1):175-85.
  2163767
• Furukawa Y, DeCaprio JA, Freedman A, Kanakura Y, Nakamura M, Ernst TJ, Livingston DM, Griffin JD.Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and noncycling human hematopoietic cells.Proc Natl Acad S
  2320588
• Ludlow JW, Shon J, Pipas JM, Livingston DM, DeCaprio JA.The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T.Cell 1990 Feb 9;60(3):387-96.
  2154332
• DeCaprio JA, Ludlow JW, Lynch D, Furukawa Y, Griffin J, Piwnica-Worms H, Huang CM, Livingston DM.The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element.Cell 1989 Sep 22;58(6):1085-95.
  2673542
• Ewen ME, Ludlow JW, Marsilio E, DeCaprio JA, Millikan RC, Cheng SH, Paucha E, Livingston DM.An N-terminal transformation-governing sequence of SV40 large T antigen contributes to the binding of both p110Rb and a second cellular protein, p120.Cell 1989 Jul
  2526683
• Ludlow JW, DeCaprio JA, Huang CM, Lee WH, Paucha E, Livingston DM.SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family.Cell 1989 Jan 13;56(1):57-65.
  2910497