Zeb1 links epithelial-mesenchymal transition and cellular senescence
Zeb1 links epithelial-mesenchymal transition and cellular senescence
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DOI：
10.1242/dev.007047
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发表时间：
2008-02-01
期刊：
影响因子：
4.6
通讯作者：
Dean, Douglas C.
中科院分区：
文献类型：
--
作者：
Liu, Yongqing;El-Naggar, Shahenda;Dean, Douglas C.
锌指E盒结合同源盒转录因子1(ZEB1)在肿瘤中的过度表达导致上皮向间充质转化(EMT)和增加转移。与过度表达相反，我们发现ZEB1突变会导致小鼠间充质-上皮细胞基因表达的转变，其特征是上皮性基因如E-钙粘附素的异位表达和间质基因如波形蛋白的表达缺失。与ZEB1过度表达的癌细胞快速增殖相反，突变小鼠的这种间充质-上皮转变与发育缺陷部位的祖细胞增殖减少有关，包括形成腭部、骨骼和中枢神经系统。ZEB1剂量依赖的上皮和间充质基因的去调控延伸到小鼠胚胎成纤维细胞(MEF)，突变的MEF在培养中也表现出复制能力降低，导致过早衰老。MEF中的复制性衰老通常是由Ink4a(CDKN2a)基因的产物触发的。然而，在ZEB1突变的MEF的衰老过程中，Ink4a途径不被激活。相反，还有另外两种细胞周期抑制蛋白依赖性激酶抑制因子p15INK4b(CDKN2B)和p21CDKN1a(CDKN1A)的异位表达。我们证明，p15INK4b的这种异位表达在体内延伸到ZEB1缺失小鼠的祖细胞增殖减弱和发育缺陷的部位。
Overexpression of zinc finger E-box binding homeobox transcription factor 1 (Zeb1) in cancer leads to epithelial-to-mesenchymal transition (EMT) and increased metastasis. As opposed to overexpression, we show that mutation of Zeb1 in mice causes a mesenchymal-epithelial transition in gene expression characterized by ectopic expression of epithelial genes such as E-cadherin and loss of expression of mesenchymal genes such as vimentin. In contrast to rapid proliferation in cancer cells where Zeb1 is overexpressed, this mesenchymal-epithelial transition in mutant mice is associated with diminished proliferation of progenitor cells at sites of developmental defects, including the forming palate, skeleton and CNS. Zeb1 dosage-dependent deregulation of epithelial and mesenchymal genes extends to mouse embryonic fibroblasts (MEFs), and mutant MEFs also display diminished replicative capacity in culture, leading to premature senescence. Replicative senescence in MEFs is classically triggered by products of the Ink4a (Cdkn2a) gene. However, this Ink4a pathway is not activated during senescence of Zeb1 mutant MEFs. Instead, there ectopic expression of two other cell cycle inhibitory cyclin-dependent kinase inhibitors, p15Ink4b (Cdkn2b) and p21Cdkn1a (Cdkn1a). We demonstrate that this ectopic expression of p15Ink4b extends in vivo to sites of diminished progenitor cell proliferation and developmental defects in Zeb1-null mice.