TY - JOUR T1 - HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. JF - Proc Natl Acad Sci U S A Y1 - 2007 A1 - Wei, Guangwei A1 - Ku, Stephen A1 - Ma, Gene K A1 - Saito, Shin'ichi A1 - Tang, Amy A A1 - Zhang, Jiasheng A1 - Jiang-Hua Mao A1 - Appella, Ettore A1 - Balmain, Allan A1 - Huang, Eric J KW - Animals KW - beta Catenin KW - Carrier Proteins KW - Cell Proliferation KW - Cells, Cultured KW - Cyclin D1 KW - Epidermis KW - Keratinocytes KW - Lymphoid Enhancer-Binding Factor 1 KW - Mice KW - Protein-Serine-Threonine Kinases KW - Repressor Proteins KW - Skin Neoplasms KW - Stem Cells KW - Transcriptional Activation AB -

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 G1-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G1-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.

VL - 104 IS - 32 U1 - http://www.ncbi.nlm.nih.gov/pubmed/17666529?dopt=Abstract ER -