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HIPK2 represses o-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis

, : HIPK2 represses o-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America7 104(32): 13040-13045

Transcriptional control by o-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-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G-S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/o-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/o-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/o-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis.


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