Notch signaling is necessary for epithelial growth arrest by TGF-β

Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
The Journal of Cell Biology (Impact Factor: 9.69). 03/2007; 176(5):695-707. DOI: 10.1083/jcb.200612129
Source: PubMed

ABSTRACT Transforming growth factor beta (TGF-beta) and Notch act as tumor suppressors by inhibiting epithelial cell proliferation. TGF-beta additionally promotes tumor invasiveness and metastasis, whereas Notch supports oncogenic growth. We demonstrate that TGF-beta and ectopic Notch1 receptor cooperatively arrest epithelial growth, whereas endogenous Notch signaling was found to be required for TGF-beta 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-beta 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-beta and endogenous levels of the Notch effector CSL contribute to p21 induction and epithelial cytostasis. Cooperative inhibition of cell proliferation by TGF-beta 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-beta.

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Available from: Hideki Niimi, Aug 03, 2015
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    • "We therefore explored the possibility that TGF-␤1 signaling induces the expression of miR-21, which could in turn limit TGF-␤1 effects in a negative feedback manner. The TGF-␤1-sensitive human keratinocyte cell line HaCaT, a well-established model for studying TGF-␤1-mediated induction of p21 CIP1 expression and growth arrest, was chosen to examine whether TGF-␤1 affected miR-21 expression (Kortlever et al., 2008; Niimi et al., 2007). HaCaT cells were stimulated with TGF-␤1 at concentration of 2 ng/ml for 24 h. "
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    • "Besides p63, Smad proteins have also been shown to functionally and biochemically interact with activated Notch1 (Blokzijl et al., 2003; Itoh et al., 2004; Zavadil et al., 2004). This can be relevant for the tumor suppressing function discussed below, as recent results point to the synergism of Notch and TGF-β signaling in keratinocyte growth inhibition, with p21 WAF1/Cip1 as an important downstream target (Niimi et al., 2007). "
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