HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis.
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.
Department of Pathology, University of California and Pathology Service 113B, Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Guangwei
G
Wei
Stephen
S
Ku
Gene K
GK
Ma
Shin'ichi
S
Saito
Amy A
AA
Tang
Jiasheng
J
Zhang
Jian-Hua
JH
Mao
Ettore
E
Appella
Allan
A
Balmain
Eric J
EJ
Huang
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics; D000078404:Epidermal Cells; D015603:Keratinocytes / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000502:physiology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D012878:Skin Neoplasms / Q000517:prevention & control*; D013234:Stem Cells / Q000166:cytology*; D015533:Transcriptional Activation; D051176:beta Catenin / Q000502:physiology*
D002352:Carrier Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D012097:Repressor Proteins; D051176:beta Catenin; D019938:Cyclin D1; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases