细胞停滞
Notch信号通路
生物
细胞生物学
转化生长因子β
癌症研究
转化生长因子β信号通路
信号转导
细胞周期蛋白依赖激酶8
Notch蛋白质类
细胞生长
转化生长因子
R-SMAD
效应器
内皮糖蛋白
干细胞
遗传学
细胞毒性
体外
川地34
作者
Hideki Niimi,Katerina Pardali,Michael Vanlandewijck,Carl–Henrik Heldin,Aristidis Moustakas
标识
DOI:10.1083/jcb.200612129
摘要
Transforming growth factor β (TGF-β) and Notch act as tumor suppressors by inhibiting epithelial cell proliferation. TGF-β additionally promotes tumor invasiveness and metastasis, whereas Notch supports oncogenic growth. We demonstrate that TGF-β and ectopic Notch1 receptor cooperatively arrest epithelial growth, whereas endogenous Notch signaling was found to be required for TGF-β to elicit cytostasis. Transcriptomic analysis after blocking endogenous Notch signaling uncovered several genes, including Notch pathway components and cell cycle and apoptosis factors, whose regulation by TGF-β requires an active Notch pathway. A prominent gene coregulated by the two pathways is the cell cycle inhibitor p21. Both transcriptional induction of the Notch ligand Jagged1 by TGF-β and endogenous levels of the Notch effector CSL contribute to p21 induction and epithelial cytostasis. Cooperative inhibition of cell proliferation by TGF-β and Notch is lost in human mammary cells in which the p21 gene has been knocked out. We establish an intimate involvement of Notch signaling in the epithelial cytostatic response to TGF-β.
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