HIPK2 represses β-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis
HIPK2 represses β-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis
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DOI：
10.1073/pnas.0703213104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Huang, Eric J.
中科院分区：
文献类型：
--
作者：
Wei, Guangwei;Ku, Stephen;Huang, Eric J.
β-连环蛋白和淋巴增强子结合因子1（LEF 1）/T细胞因子的转录控制调节干细胞增殖和肿瘤发生。在这里，我们提供的证据表明，转录辅阻遏物同源结构域相互作用蛋白激酶2（HIPK 2）控制的数量的干细胞和祖细胞在皮肤和发展鳞状细胞癌的易感性。HIPK 2的缺失导致增殖潜能增加、细胞周期中更快的G（1）-S转变以及表皮干细胞区室的扩增。在细胞周期中G（1）-S转换的关键调节因子中，只有细胞周期蛋白D1在缺乏HIPK 2的细胞中选择性上调。相反，HIPK 2的过表达抑制LEF 1/β-连环蛋白介导的细胞周期蛋白D1表达的转录激活。然而，HIPK 2的C-末端YH结构域的缺失完全废除了其招募另一个转录辅抑制因子CtBP和抑制LEF 1/β-连环蛋白介导的转录的能力。为了确定HIPK 2的缺失是否导致对肿瘤发生的易感性增加，我们用两阶段致癌方案治疗野生型、Hipk 2（+/-）和Hipk 2（-/-）小鼠。我们的研究结果表明，更多的皮肤肿瘤诱导Hipk 2（+/-）和Hipk 2（-/-）突变体，与大多数肿瘤显示缩短的潜伏期和恶性进展。总之，我们的结果表明HIPK 2是通过拮抗LEF 1/β-连环蛋白介导的转录来控制增殖的肿瘤抑制因子。HIPK 2的缺失与H-ras的活化协同诱导肿瘤发生。
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 corepressor 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 LEFl/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/ p-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk2(+/-), and Hipk2(-/-) 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 LEFl/beta-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis.