25. Duncan LM, Piper S, Dodd RB, Saville MK, Sanderson CM, et al. (2006) Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. Embo J 25: 1635–1645. 26. Geetha T, Jiang J, Wooten MW (2005) Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell 20: 301–312. 27. Lauwers E, Jacob C, Andre B (2009) K63-linked ubiquitin chains as a specific signal for protein sorting into the multivesicular body pathway. J Cell Biol 185: 493–502. 28. Didier C, Broday L, Bhoumik A, Israeli S, Takahashi S, et al. (2003) RNF5, a RING finger protein that regulates cell motility by targeting paxillin ubiquitination and altered localization. Mol Cell Biol 23: 5331–5345. 29. Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD (2003) The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63- linked polyubiquitin chains. Oncogene 22: 7101–7107. 30. Tan JM, Wong ES, Kirkpatrick DS, Pletnikova O, Ko HS, et al. (2008) Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum Mol Genet 17: 431–439. 31. Fry DC, Vassilev LT (2005) Targeting protein-protein interactions for cancer therapy. J Mol Med 83: 955–963. 32. Simon RJ, Kania RS, Zuckermann RN, Huebner VD, Jewell DA, et al. (1992) Peptoids: a modular approach to drug discovery. Proc Natl Acad Sci U S A 89: 9367–9371. 33. Masip I, Cortes N, Abad MJ, Guardiola M, Perez-Paya E, et al. (2005) Design and synthesis of an optimized positional scanning library of peptoids: identification of novel multidrug resistance reversal agents. Bioorg Med Chem 13: 1923–1929. 34. Banerjee R, Basu G (2002) A short Aib/Ala-based peptide helix is as stable as an Ala-based peptide helix double its length. Chembiochem 3: 1263–1266. 35. Armand P, Kirshenbaum K, Goldsmith RA, Farr-Jones S, Barron AE, et al. (1998) NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains. Proc Natl Acad Sci U S A 95: 4309–4314. 36. Sanborn TJ, Wu CW, Zuckermann RN, Barron AE (2002) Extreme stability of helices formed by water-soluble poly-N-substituted glycines (polypeptoids) with alpha-chiral side chains. Biopolymers 63: 12–20. 37. Jang H, Fafarman A, Holub JM, Kirshenbaum K (2005) Click to fit: versatile polyvalent display on a peptidomimetic scaffold. Org Lett 7: 1951–1954. 38. Linusson A, Wold S, Norden B (1998) Statistical molecular design of peptoid libraries. Mol Divers 4: 103–114. 39. Perez C, Ortiz AR (2001) Evaluation of docking functions for protein-ligand docking. J Med Chem 44: 3768–3785. 40. McKenna S, Hu J, Moraes T, Xiao W, Ellison MJ, et al. (2003) Energetics and specificity of interactions within Ub.Uev.Ubc13 human ubiquitin conjugation complexes. Biochemistry 42: 7922–7930. 41. Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7: 758–765. 42. Rubio N, Villacampa MM, Blanco J (1998) Traffic to lymph nodes of PC-3 prostate tumor cells in nude mice visualized using the luciferase gene as a tumor cell marker. Lab Invest 78: 1315–1325. 43. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681. 44. Oost TK, Sun C, Armstrong RC, Al-Assaad AS, Betz SF, et al. (2004) Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem 47: 4417–4426. Novel Ubc13 Inhibitors 45. Sillerud LO, Larson RS (2005) Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. Curr Protein Pept Sci 6: 151–169. 46. Sun H, Nikolovska-Coleska Z, Yang CY, Xu L, Liu M, et al. (2004) Structure- based design of potent, conformationally constrained Smac mimetics. J Am Chem Soc 126: 16686–16687. 47. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844–848. 48. Gilmore TD, Herscovitch M (2006) Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 25: 6887–6899. 49. Fojo T, Bates S (2003) Strategies for reversing drug resistance. Oncogene 22: 7512–7523. 50. Grunwald V, DeGraffenried L, Russel D, Friedrichs WE, Ray RB, et al. (2002) Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 62: 6141–6145. 51. Huang H, Cheville JC, Pan Y, Roche PC, Schmidt LJ, et al. (2001) PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression. J Biol Chem 276: 38830–38836. 52. Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, et al. (2004) Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 10: 7031–7042. 53. Fukushima T, Matsuzawa S, Kress CL, Bruey JM, Krajewska M, et al. (2007) Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor- associated factor (TRAF)-mediated inflammatory responses. Proc Natl Acad Sci U S A 104: 6371–6376. 54. Zeng W, Sun L, Jiang X, Chen X, Hou F, et al. (2010) Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141: 315–330. 55. Zeng W, Xu M, Liu S, Sun L, Chen ZJ (2009) Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell 36: 315–325. 56. Huen MS, Huang J, Yuan J, Yamamoto M, Akira S, et al. (2008) Noncanonical E2 variant-independent function of UBC13 in promoting checkpoint protein assembly. Mol Cell Biol 28: 6104–6112. 57. Lay JD, Hong CC, Huang JS, Yang YY, Pao CY, et al. (2007) Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. Cancer Res 67: 3878–3887. 58. Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW (2008) Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg- 1. Oncogene. 59. Shukla S, Gupta S (2004) Suppression of constitutive and tumor necrosis factor alpha-induced nuclear factor (NF)-kappaB activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells: correlation with down- regulation of NF-kappaB-responsive genes. Clin Cancer Res 10: 3169–3178. 60. Torres J, Watt FM (2008) Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3. Nat Cell Biol 10: 194–201. 61. Plans V, Scheper J, Soler M, Loukili N, Okano Y, et al. (2006) The RING finger protein RNF8 recruits UBC13 for lysine 63-based self polyubiquitylation. J Cell Biochem 97: 572–582. 62. Pettaway CA, Pathak S, Greene G, Ramirez E, Wilson MR, et al. (1996) Selection of highly metastatic variants of different human prostatic carcinomas using orthotopic implantation in nude mice. Clin Cancer Res 2: 1627–1636. PLoS ONE | www.plosone.org 11 June 2010 | Volume 5 | Issue 6 | e11403