Cancer and Metastasis Reviews

, Volume 23, Issue 1–2, pp 41–52 | Cite as

Lymphoid enhancer factor/T cell factor expression in colorectal cancer

  • Marian L. Waterman
Article

Abstract

Genetic inactivation of key components of the Wnt signal transduction system is a frequent event in colorectal cancer. These genetic mutations lead to stabilization of β-catenin, a cytoplasmic–nuclear shuttling protein with a potent transcription activation domain. Stabilization and subsequent nuclear localization of β-catenin produces aberrant, Wnt-independent signals to target genes, an activity tightly linked to the genesis of colon cancers. In the nucleus, the transcription factor family of LEF/TCF proteins transmits Wnt signals by binding to β-catenin and recruiting it to target genes for activation. Such activities are carried out by full-length LEF/TCFs that are thought to be mostly interchangeable and redundant. However, truncated forms of LEF-1 and TCF-1 that do not bind to β-catenin function as dominant negatives and an alternatively spliced TCF isoform with a unique activation function has recently been discovered. The dominant negative forms block Wnt signals because they occupy Wnt target genes and limit β-catenin access; the alternatively spliced TCF isoform activates certain Wnt target promoters whereas other TCF isoforms and LEF-1 do not. A study of LEF/TCF expression and activity in normal intestine and colon carcinomas suggests that the relative amounts of LEF/TCF isoforms may change as tumors progress and this may influence the strength and specificity of Wnt signals in the nucleus. While the underlying mechanism for a change in the LEF/TCF isoform expression is not yet known, recent evidence implicates the Wnt signaling pathway itself as a potential modulator.

colon HMG LEF TCF Wnt β-catenin 

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References

  1. 1.
    Polakis P: Wnt signaling and cancer. Genes Dev. 14: 1837–1851, 2000Google Scholar
  2. 2.
    Peifer M, Polakis P: Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 287: 1606–1609, 2000Google Scholar
  3. 3.
    Taipale J, Beachy PA: The Hedgehog and Wnt signaling pathways in cancer. Nature 411: 349–354, 2001Google Scholar
  4. 4.
    Bienz M, Clevers H: Linking colorectal cancer to Wnt signaling. Cell 103: 311–320, 2000Google Scholar
  5. 5.
    Groden J: Touch and go: Mediating cell-to-cell interactions and Wnt signaling in gastrointestinal tumor formation. Gastroenterology 119: 1161–1164, 2000Google Scholar
  6. 6.
    Barker N, Clevers H: Catenins, Wnt signaling and cancer. BioEssays 22: 961–965, 2000Google Scholar
  7. 7.
    Moon RT, Bowerman B, Boutros M, Perrimon N: The promise and perils of Wnt signaling through beta-catenin. Science 296: 1644–1646, 2002Google Scholar
  8. 8.
    Henderson BR, Fagotto F: The ins and outs of APC and ta-catenin nuclear transport. EMBO Rep 3: 834–839, 2002Google Scholar
  9. 9.
    Woodgett J: Regulation and functions of the glycogen synthase kinase-3 subfamily. Sem. Cancer Biol 5: 269–275, 1994Google Scholar
  10. 10.
    Cook D, Fry M, Hughes K, Sumathipala R, Woodgett J, Dale T: Wingless inactivates glycogen synthase kinase-3 via an intracellular signaling pathway which involves a protein kinase C. Embo J 15: 4526–4536, 1996Google Scholar
  11. 11.
    Harwood AJ: Regulation of GSK-3: A cellular multi-processor. Cell 105: 821–824, 2001Google Scholar
  12. 12.
    Su LK, Vogelstein B, Kinzler KW: Association of the APC tumor suppressor protein with catenins. Science 262: 1734–1737, 1993Google Scholar
  13. 13.
    Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P: Association of the APC gene product with beta-catenin. Science 262: 1731–1734, 1993Google Scholar
  14. 14.
    Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F: The mouse fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90: 181–192, 1997Google Scholar
  15. 15.
    Behrens J, Jerchow B-A, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhn M, Wedlich D, Birchmeier W: Functional interaction of an axin homolog, conductin, with β-catenin, APC and GSK3β. Science 280: 596–599, 1998Google Scholar
  16. 16.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X: Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108: 837–847, 2002Google Scholar
  17. 17.
    Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I: Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: A molecular switch for the Wnt pathway. Genes Dev 16: 1066–1076, 2002Google Scholar
  18. 18.
    Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P: Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 8: 573–581, 1998Google Scholar
  19. 19.
    Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A: Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J 17: 1371–1384, 1998Google Scholar
  20. 20.
    Sakanaka C, Leong P, Xu L, Harrison SD, Williams LT: Casein kinase iepsilon in the wnt pathway: Regulation of beta-catenin function. Proc Natl Acad Sci USA 96: 12548–12552, 1999Google Scholar
  21. 21.
    Sakanaka C, Weiss JB, Williams LT: Bridging of betacatenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proc Natl Acad Sci USA 95: 3020–3023, 1998Google Scholar
  22. 22.
    von Kries JP, Winbeck G, Asbrand C, Schwarz-Romond T, Sochnikova N, Dell'Oro A, Behrens J, Birchmeier W: Hot spots in beta-catenin for interactions with LEF-1, conductin and APC. Nat Struct Biol 7: 800–807, 2000Google Scholar
  23. 23.
    van Noort M, Clevers H: TCF transcription factors, mediators of Wnt-signaling in development and cancer. Dev Biol 244: 1–8, 2002Google Scholar
  24. 24.
    Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, van de Wetering M, Pawson T, Clevers H: Beta-Catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell, 111: 251–263, 2002Google Scholar
  25. 25.
    van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H: The beta-Catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111: 241–250, 2002Google Scholar
  26. 26.
    Brown AM: Wnt signaling in breast cancer: Have we come full circle? Breast Cancer Res 3: 351–355, 2001Google Scholar
  27. 27.
    Aoki M, Hecht A, Kruse U, Kemler R, Vogt PK: Nuclear endpoint of Wnt signaling: Neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. Proc Natl Acad Sci USA 96: 139–144, 1999Google Scholar
  28. 28.
    Chan EF, Gat U, McNiff JM, Fuchs E: A common human skin tumor is caused by activating mutations in betacatenin. Nat Genet 21: 410–413, 1999Google Scholar
  29. 29.
    Gat U, DasGupta R, Degenstein L, Fuchs E: De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95: 605–614, 1998Google Scholar
  30. 30.
    Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ: WISP-1 is a Wnt-1-and beta-catenin-responsive oncogene. Genes Dev 14: 585–595, 2000Google Scholar
  31. 31.
    Tao W, Pennica D, Xu L, Kalejta RF, Levine AJ: Wrch-1, a novel member of the Rho gene familythat is regulated by Wnt-1. Genes Dev 15: 1796–1807, 2001Google Scholar
  32. 32.
    Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T, Ohgi KA, Lin C, Gleiberman A, Wang J, Brault V, Ruiz-Lozano P, Nguyen HD, Kemler R, Glass CK, Wynshaw-Boris A, Rosenfeld MG: Identification of a Wnt/Dvl/beta-Catenin ? Pitx2 pathwaymediating cell-type-specific proliferation during development. Cell 111: 673–685, 2002Google Scholar
  33. 33.
    Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H, Matsumoto K: The TAK1-NLK-MAPK-related pathwayantagonizes signaling between beta-catenin and transcription factor TCF. Nature 399: 798–802, 1999Google Scholar
  34. 34.
    Snider L, Thirlwell H, Miller JR, Moon RT, Groudine M, Tapscott SJ: Inhibition of Tcf3 binding by I-mfa domain proteins. Mol Cell Biol 21: 1866–1873, 2001Google Scholar
  35. 35.
    Tago K, Nakamura T, Nishita M, Hyodo J, Nagai S, Murata Y, Adachi S, Ohwada S, Morishita Y, Shibuya H, Akiyama T: Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev 14: 1741–1749, 2000Google Scholar
  36. 36.
    Sampson EM, Haque ZK, Ku MC, Tevosian SG, Albanese C, Pestell RG, Paulson KE, Yee AS: Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1. EMBO J 20: 4500–4511, 2001Google Scholar
  37. 37.
    Hatini V, Bokor P, Goto-Mandeville R, DiNardo S: Tissue-and stage-specific modulation of Wingless signaling bythe segment polarity gene lines. Genes Dev 14: 1364–1376, 2000Google Scholar
  38. 38.
    Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE: Regulation of Wnt signaling bySox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol Cell 4: 487–498, 1999Google Scholar
  39. 39.
    Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Zullig S, Basler K: Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 109: 47–60, 2002Google Scholar
  40. 40.
    Parker DS, Jemison J, Cadigan KM: Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development 129: 2565–2576, 2002Google Scholar
  41. 41.
    Thompson B, Townsley F, Rosin-Arbesfeld R, Musisi H, Bienz M: A new nuclear component of the Wnt signaling pathway. Nat Cell Biol 4: 367–373, 2002Google Scholar
  42. 42.
    Belenkaya TY, Han C, Standley HJ, Lin X, Houston DW, Heasman J: Pygopus encodes a nuclear protein essential for wingless/Wnt signaling. Development 129: 4089–4101, 2002Google Scholar
  43. 43.
    Waterman ML, Fischer WH, Jones KA: A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer. Genes Dev 5: 656–669, 1991Google Scholar
  44. 44.
    Travis A, Amsterdam A, Belanger C, Grosschedl R: LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function. Genes Dev 5: 880–894, 1991Google Scholar
  45. 45.
    van de Wetering M, Oosterwegel M, Dooijes D, Clevers H: Identification and cloning of TCF-1, a T lymphocyte specific transcription factor containing a sequence-specific HMG box. EMBO J 10: 123–132, 1991Google Scholar
  46. 46.
    Korinek V, Barker N, Willert K, Molenaar M, Roose J, Wagenaar G, Markman M, Lamers W, Destree O, Clevers H: Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse. Mol Cell Biol 18: 1248–1256, 1998Google Scholar
  47. 47.
    Oosterwegel M, van de Wetering M, Timmerman J, Kruisbeek A, Destree O, Meijlink F, Clevers H: Differential expression of the HMG box factors TCF-1 and LEF-1 during murine embryogenesis. Development 118: 439–448, 1993Google Scholar
  48. 48.
    Reya T, O'Riordan M, Okamura R, Devaney E, Willert K, Nusse R, Grosschedl R: Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity 13: 15–24, 2000Google Scholar
  49. 49.
    Zhou P, Byrne C, Jacobs J, Fuchs E: Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev 9: 700–713, 1995Google Scholar
  50. 50.
    chanMerrill BJ, Gat U, DasGupta R, Fuchs E: Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev 15: 1688–1705, 2001Google Scholar
  51. 51.
    Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Lawrence Marsh J, Holcombe RF, Waterman ML: Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet 28: 53–57, 2001Google Scholar
  52. 52.
    Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, Logtenberg T, Clevers H: Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 285: 1923–1926, 1999Google Scholar
  53. 53.
    Porfiri E, Rubinfeld B, Albert I, Hovanes K, Waterman M, Polakis P: Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. Oncogene 15: 2833–2839, 1997Google Scholar
  54. 54.
    Barker N, Huls G, Korinek V, Clevers H: Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium. Am J Pathol 154: 29–35, 1999Google Scholar
  55. 55.
    Bustin M, Reeves R: High-mobility-group chromosomal proteins: Architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol 54: 35–100, 1996Google Scholar
  56. 56.
    Giese K, Amsterdam A, Grosschedl R: DNA-binding properties of the HMG domain of the lymphoid-specific transcriptional regulator LEF-1. Genes Dev 5: 2567–2578, 1991Google Scholar
  57. 57.
    Giese K, Cox J, Grosscheldl R: The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell 69: 185–196, 1992Google Scholar
  58. 58.
    van de Wetering M, Clevers H: Sequence-specific interaction of the HMG box proteins TCF-1 and SRY occurs within the minor groove of a Watson-Crick double helix. EMBO J 11: 3039–3044, 1992Google Scholar
  59. 59.
    van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H: Armadillo coactivates transcription driven bythe product of the Drosophila segment polaritygene dTCF. Cell 88: 789–799, 1997Google Scholar
  60. 60.
    Love JJ, Li X, Case DA, Giese K, Grosschedl R, Wright PE: Structural basis for DNA bending by the architectural transcription factor LEF-1. Nature 376: 791–795, 1995Google Scholar
  61. 61.
    Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H: XTCF-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell 86: 391–399, 1996Google Scholar
  62. 62.
    Behrens J, von Kries JP, Kuh M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W: Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382: 638–642, 1996Google Scholar
  63. 63.
    Brunner E, Peter O, Schweizer L, Basler K: Pangolin encodes a LEF-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila. Nature 385: 829–833, 1997Google Scholar
  64. 64.
    Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W: Tcf4 can specifically recognize beta-catenin using alternative conformations. Nat Struct Biol 8: 1048–1052, 2001Google Scholar
  65. 65.
    Graham TA, Weaver C, Mao F, Kimelman D, Xu W: Crystal structure of a beta-catenin/Tcf complex. Cell 103: 885–896, 2000Google Scholar
  66. 66.
    van de Wetering M, Castrop J, Korinek V, Clevers H: Extensive alternative splicing and dual promoter usage generate Tcf-protein isoforms with differential transcription control properties. Mol Cell Biol 16: 745–752, 1996Google Scholar
  67. 67.
    Duval A, Rolland S, Tubacher E, Bui H, Thomas G, Hamelin R: The human T-cell transcription factor-4 gene: Structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines. Cancer Res 60: 3872–3879, 2000Google Scholar
  68. 68.
    Hovanes K, Li TWH, Waterman ML: The human LEF-1 gene contains a promoter preferentiallyactive in lymphocytes and encodes multiple isoforms derived from alternative splicing. Nucleic Acids Res 28: 1994–2003, 2000Google Scholar
  69. 69.
    Brannon M, Brown JD, Bates R, Kimelman D, Moon RT: XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development. Development 126: 3159–3170, 1999Google Scholar
  70. 70.
    Kumar V, Carlson JE, Ohgi KA, Edwards TA, Rose DW, Escalante CR, Rosenfeld MG, Aggarwal AK: Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase. Mol Cell 10: 857–869, 2002Google Scholar
  71. 71.
    Kim GT, Shoda K, Tsuge T, Cho KH, Uchimiya H, Yokoyama R, Nishitani K, Tsukaya H: The ANGUSTI-FOLIA gene of Arabidopsis, a plant CtBP gene, regulates leaf-cell expansion, the arrangement of cortical microtubules in leaf cells and expression of a gene involved in cell-wall formation. EMBO J 21: 1267–1279, 2002Google Scholar
  72. 72.
    Folkers U, Kirik V, Schobinger U, Falk S, Krishnakumar S, Pollock MA, Oppenheimer DG, Day I, Reddy AS, Jurgens G, Hulskamp M, Reddy AR: The cell morphogenesis gene Angustifolia encodes a CtBP/BARS-like protein and is involved in the control of the microtubule cytoskeleton. EMBO J 21: 1280–1288, 2002Google Scholar
  73. 73.
    Zhang Q, Piston DW, Goodman RH: Regulation of corepressor function by nuclear NADH. Science 295: 1895–1897, 2002Google Scholar
  74. 74.
    Hecht A, Stemmler MP: Identification of a promoter-specific transcriptional activation domain at the C terminus of the Wnt effector protein T-cell factor 4. J Biol Chem 278: 3776–3785, 2003Google Scholar
  75. 75.
    Atcha FA, Munguia JE, Li TW, Hovanes K, Waterman ML: A new beta-catenin dependent activation domain in T cell factor. J Biol Chem 2003Google Scholar
  76. 76.
    Giese K, Kingsley C, Kirshner JR, Grosschedl R: Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev 9: 995–1008, 1995Google Scholar
  77. 77.
    Grosschedl R, Giese K, Pagel J: HMG domain proteins: Architectural elements in the assembly of nucleoprotein structures. Trends Genet 10: 94–100, 1994Google Scholar
  78. 78.
    Brantjes H, Roose J, van De Wetering M, Clevers H: All TCF HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res 29: 1410–1419, 2001Google Scholar
  79. 79.
    Billin AN, Thirlwell H, Ayer DE: Beta-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator. Mol Cell Biol 20: 6882–6890, 2000Google Scholar
  80. 80.
    Bruhn L, Munnerly A, Grosschedl R: ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCR alpha enhancer function. Genes Dev 11: 640–653, 1997Google Scholar
  81. 81.
    Giese K, Grosschedl R: LEF-1 contains an activation domain that stimulates transcription onlyin a specific context of factor-binding sites. EMBO J 12: 4667–4676, 1993Google Scholar
  82. 82.
    Carlsson P, Waterman M, Jones K: The hLEF/TCF-1a HMG protein contains a context-dependent transcriptional activation domain that induces the TCRa enhancer in T cells. Genes Dev 7: 2418–2430, 1993Google Scholar
  83. 83.
    Mayall TP, Sheridan PL, Montminy MR, KA J: Distinct Roles for P-CREB and LEF-1 in TCR alpha enhancer assembly and activation on chromatin templates In Vitro. Genes and Dev 11: 887–899, 1997Google Scholar
  84. 84.
    Castrop J, van Wichen D, Koomans-Bitter M, van de Wetering M, de Weger R, van Dongen J, Clevers H: The human TCF-1 gene encodes a nuclear DNA-binding protein uniquely expressed in normal and neoplastic T-lineage lymphocytes. Blood 86: 3050–3059, 1995Google Scholar
  85. 85.
    Korinek V, Barker N, Morin P, van Wichen D, de Weger R, Kinzler K, Vogelstein B, Clevers H: Constitutive transcriptional activation bya beta-catenin-Tcf complex in APC-/-colon carcinoma. Science 275: 1784–1787, 1997Google Scholar
  86. 86.
    Mayer K, Hieronymus T, Castrop J, Clevers H, Ballhausen W: Ectopic activation of lymphoid high mobility groupbox transcription factor TCF-1 and overexpression in colorectal cancer cells. Int J Cancer 72: 625–630, 1997Google Scholar
  87. 87.
    van Genderen C, Okamura R, Farinas I, Quo R, Parslow T, Bruhn L, Grosschedl R: Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 8: 2691–2703, 1994Google Scholar
  88. 88.
    Wong MH, Huelsken J, Birchmeier W, Gordon JI: Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkuhn is perturbed by stimulation of Lef-1/beta-catenin signaling. J Biol Chem 277: 15843–15850, 2002Google Scholar
  89. 89.
    Aberle H, Bauer A, Stappert J, Kispert A, Kemler R: Betacatenin is a target for the ubiquitin-proteasome pathway. EMBO J 16: 3797–3804, 1997Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Marian L. Waterman
    • 1
  1. 1.Department of Microbiology and Molecular Genetics, College of MedicineUniversity of California, IrvineIrvineUSA

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