title: A variant of Smurf2 protects mice against colitis-associated colon cancer by inducing transforming growth factor β signaling.
abstract: OBJECTIVE
  Transforming growth factor (TGF)-β signaling, which is down-regulated by the E3 ubiquitin ligase Smad ubiquitin regulating factor 2 (Smurf2), promotes development of cancer. We identified a splice variant of Smurf2 (ΔE2Smurf2) and investigated its role in colon carcinogenesis in mice.
  
  
  METHODS
  Colitis-associated colon cancer was induced in mice by administration of azoxymethane, followed by 3 cycles of oral administration of dextran sodium sulfate. Messenger RNA levels of Smurf2 in colon tumors and control tissue were measured by quantitative polymerase chain reaction; lymphocyte and cytokine levels were measured in tumor and tissue samples.
  
  
  RESULTS
  Tumor-infiltrating CD4(+) cells expressed higher levels of ΔE2Smurf2 than CD4(+) cells from nontumor tissues of wild-type mice. T cell-specific overexpression of ΔE2Smurf2 increased TGF-β signaling by suppressing protein levels of Smurf2, accompanied by an increase in levels of TGF-β receptor type II. Transgenic mice that overexpress ΔE2Smurf2 were protected against development of colitis-associated tumors and down-regulated proinflammatory cytokines such as interleukin-6. Patients with chronic inflammatory bowel disease had a significantly lower ratio of Smurf2/ΔE2Smurf2 than control individuals.
  
  
  CONCLUSIONS
  T cell-specific ΔE2Smurf2 degrades wild-type Smurf2 and controls intestinal tumor growth in mice by up-regulating TGF-β receptor type II, reducing proliferation and production of proinflammatory cytokines.
authors.affiliation: Department of Medicine, University of Erlangen-Nuremberg, Erlangen and Nuremberg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Dornhoff
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosfa
authors.forename: Clemens
authors.initials: C
authors.lastname: Neufert
authors.forename: Jonas
authors.initials: J
authors.lastname: Mudter
authors.forename: Jürgen
authors.initials: J
authors.lastname: Markl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Siebler
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000517:prevention & control*; D020869:Gene Expression Profiling; D018960:Hyaluronan Receptors / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016212:Transforming Growth Factor beta; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D019009:Proto-Oncogene Proteins c-kit