| First Author | Dornhoff H | Year | 2012 |
| Journal | Gastroenterology | Volume | 142 |
| Issue | 5 | Pages | 1183-1194.e4 |
| PubMed ID | 22333948 | Mgi Jnum | J:311781 |
| Mgi Id | MGI:6780417 | Doi | 10.1053/j.gastro.2012.02.005 |
| Citation | Dornhoff H, et al. (2012) A variant of Smurf2 protects mice against colitis-associated colon cancer by inducing transforming growth factor beta signaling. Gastroenterology 142(5):1183-1194.e4 |
| abstractText | BACKGROUND & AIMS: Transforming growth factor (TGF)-beta 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 (DeltaE2Smurf2) 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 DeltaE2Smurf2 than CD4(+) cells from nontumor tissues of wild-type mice. T cell-specific overexpression of DeltaE2Smurf2 increased TGF-beta signaling by suppressing protein levels of Smurf2, accompanied by an increase in levels of TGF-beta receptor type II. Transgenic mice that overexpress DeltaE2Smurf2 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/DeltaE2Smurf2 than control individuals. CONCLUSIONS: T cell-specific DeltaE2Smurf2 degrades wild-type Smurf2 and controls intestinal tumor growth in mice by up-regulating TGF-beta receptor type II, reducing proliferation and production of proinflammatory cytokines. |
