Acute Overexpression of Myc in Intestinal Epithelium Recapitulates Some but Not All the Changes Elicited by Wnt/β-Catenin Pathway Activation
Acute Overexpression of Myc in Intestinal Epithelium Recapitulates Some but Not All the Changes Elicited by Wnt/β-Catenin Pathway Activation
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DOI：
10.1128/mcb.01745-08
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发表时间：
2009-10-01
影响因子：
5.3
通讯作者：
Evan, Gerard I.
中科院分区：
文献类型：
--
作者：
Finch, Andrew J.;Soucek, Laura;Evan, Gerard I.
Myc转录因子是一种强大的增殖诱导剂，是肠上皮细胞Wnt/β-catenin信号转导所必需的。由于Wnt/β-catenin通路的失控是非遗传性肠道肿瘤发生的先决条件，我们询问Myc的激活是否重现了结肠腺瘤性息肉病(APC)失活后由结构性Wnt/β-catenin通路信号驱动的致瘤变化。在肠道上皮细胞中转基因表达MycER()的小鼠，我们定义了Myc激活和随后失活后的急性变化。MYC激活可逆地概括了APC失活的许多(但不是全部)方面，包括增加增殖和凋亡以及杯状细胞的丢失。然而，APC失活会导致Paneth细胞的重新分布，而Myc的直接激活会触发它们的快速磨损。此外，Myc的直接激活参与了ARF/P53/p21(Cip1)肿瘤抑制通路，而Wnt/β-catenin信号的解除调节不参与。这些观察结果说明了通过Wnt/β-catenin途径直接激活Myc和间接激活Myc对肠上皮细胞致癌影响的关键差异。此外，Myc诱导的成熟杯状细胞的原位去分化表明Wnt/β-catenin和Notch信号通路之间存在新的串扰。
The Myc transcription factor is a potent inducer of proliferation and is required for Wnt/beta-catenin signaling in intestinal epithelium. Since deregulation of the Wnt/beta-catenin pathway is a prerequisite for nonhereditary intestinal tumorigenesis, we asked whether activation of Myc recapitulates the tumorigenic changes that are driven by constitutive Wnt/beta-catenin pathway signaling following adenomatous polyposis coli (APC) inactivation. Using mice in which expression of MycER(TAM), a reversibly switchable form of Myc, is expressed transgenically in intestinal epithelium, we define the acute changes that follow Myc activation as well as subsequent deactivation. Myc activation reversibly recapitulates many, but not all, aspects of APC inactivation, including increased proliferation and apoptosis and loss of goblet cells. However, whereas APC inactivation induces redistribution of Paneth cells, direct Myc activation triggers their rapid attrition. Moreover, direct Myc activation engages the ARF/p53/p21(cip1) tumor suppressor pathway, whereas deregulation of Wnt/beta-catenin signaling does not. These observations illustrate key differences in oncogenic impact in intestinal epithelium of direct Myc activation and indirect Myc activation via the Wnt/beta-catenin pathway. Furthermore, the in situ dedifferentiation of mature goblet cells that Myc induces indicates a novel cross talk between the Wnt/beta-catenin and Notch signaling pathways.