| First Author | Wei G | Year | 2007 |
| Journal | Proc Natl Acad Sci U S A | Volume | 104 |
| Issue | 32 | Pages | 13040-5 |
| PubMed ID | 17666529 | Mgi Jnum | J:123698 |
| Mgi Id | MGI:3719306 | Doi | 10.1073/pnas.0703213104 |
| Citation | Wei G, et al. (2007) HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proc Natl Acad Sci U S A 104(32):13040-5 |
| abstractText | Transcriptional control by beta-catenin and lymphoid enhancer-binding factor 1 (LEF1)/T cell factor regulates proliferation in stem cells and tumorigenesis. Here we provide evidence that transcriptional co repressor homeodomain interacting protein kinase 2 (HIPK2) controls the number of stem and progenitor cells in the skin and the susceptibility to develop squamous cell carcinoma. Loss of HIPK2 leads to increased proliferative potential, more rapid G(1)-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G(1)-S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/beta-catenin-mediated transcriptional activation of cyclin D1 expression. However, deletion of the C-terminal YH domain of HIPK2 completely abolishes its ability to recruit another transcriptional corepressor CtBP and suppress LEF1/beta-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk2(+/-), andHipk2(-/-) mice with the two-stage carcinogenesis protocol. Our results indicate that more skin tumors are induced in Hipk2(+/-) and Hipk2(-/-) mutants, with most of the tumors showing shortened incubation time and malignant progression. Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/beta-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis. |
