KLF4 周转率的调节揭示了 pVHL 在肿瘤发生中具有意想不到的组织特异性作用。
Regulation of KLF4 turnover reveals an unexpected tissue-specific role of pVHL in tumorigenesis.
机构信息
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
出版信息
Mol Cell. 2012 Jan 27;45(2):233-43. doi: 10.1016/j.molcel.2011.11.031.
The transcription factor Krüppel-like factor 4 (KLF4) is an important regulator of cell-fate decision, including cell-cycle regulation, apoptosis, and stem cell renewal, and plays an ambivalent role in tumorigenesis as a tissue-specific tumor suppressor or oncogene. Here, we report that the Von Hippel-Lindau gene product, pVHL, physically interacts with KLF4 and regulates its rapid turnover observed in both differentiated and stem cells. We provide mechanistic insights into KLF4 degradation and show that pVHL depletion in colorectal cancer cells leads to cell-cycle arrest concomitant with increased transcription of the KLF4-dependent p21 gene. Finally, immunohistochemical staining revealed elevated pVHL and reduced KLF4 levels in colon cancer tissues. We therefore propose that unexpectedly pVHL, via the degradation of KLF4, is a facilitating factor in colorectal tumorigenesis.
转录因子 Krüppel 样因子 4（KLF4）是细胞命运决定的重要调节剂，包括细胞周期调节、细胞凋亡和干细胞更新，并在肿瘤发生中作为组织特异性肿瘤抑制因子或癌基因发挥双重作用。在这里，我们报告称，Von Hippel-Lindau 基因产物 pVHL 与 KLF4 物理相互作用，并调节其在分化细胞和干细胞中观察到的快速周转。我们提供了 KLF4 降解的机制见解，并表明在结直肠癌细胞中耗尽 pVHL 会导致细胞周期停滞，同时增加 KLF4 依赖性 p21 基因的转录。最后，免疫组织化学染色显示结肠癌组织中 pVHL 升高和 KLF4 水平降低。因此，我们提出，出乎意料的是，pVHL 通过降解 KLF4，是结直肠肿瘤发生的促进因素。
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