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.
Notch signaling is necessary for epithelial growth arrest by TGF-β
H. Niimi and K. Pardali contributed equally to this paper.
H. Niimi's present address is Toyama University Faculty of Medicine, Dept. of Clinical and Molecular Pathology, Toyama City 930-0194, Japan.
K. Pardali's present address is Molecular Medicine, Dept. of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
Abbreviations used in this paper: GAPDH, glyceraldehyde-3′-phosphate dehydrogenase; GSI, γ-secretase inhibitor; HMEC, human mammary epithelial cell; MOI, multiplicity of infection; N1ICD, Notch1 intracellular domain.
Hideki Niimi, Katerina Pardali, Michael Vanlandewijck, Carl-Henrik Heldin, Aristidis Moustakas; Notch signaling is necessary for epithelial growth arrest by TGF-β . J Cell Biol 26 February 2007; 176 (5): 695–707. doi: https://doi.org/10.1083/jcb.200612129
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