Notch signaling is necessary for epithelial growth arrest by TGF-

Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
The Journal of Cell Biology (Impact Factor: 9.83). 03/2007; 176(5):695-707. DOI: 10.1083/jcb.200612129
Source: PubMed


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.

Download full-text


Available from: Hideki Niimi, Oct 05, 2015
37 Reads
  • Source
    • "In addition, Notch could induce EMT by stabilizing Snail-1 protein under hypoxic condition.63 It has been reported that Slug is a direct target of Notch and that the Notch directly stimulates the Slug promoter, resulting in the upregulation of Slug and initiation of EMT.64 Slug was found to be essential for Notch-mediated repression of E-cadherin, resulting in β-catenin activation and EMT.65 It has been reported that TGF-β can induce the expression of Notch ligands66 and that TGF-β-induced EMT could be blocked by Hey-1 or Jagged-1 knockdown or by pharmacological inactivation of Notch.67 Notch-2 and Jagged-1 are highly upregulated in gemcitabine-resistant pancreatic cancer cells, which show acquisition of an EMT phenotype.68 Recently, EMT has been mechanistically linked with stem-like signatures in prostate cancer cells,69 with stem-like cells characterized by increased expression of Notch-1, Sox2, Nanog, Oct4, and Lin28B.69 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Notch signaling is an evolutionarily conserved pathway involved in cell fate control during development, stem cell self-renewal, and postnatal tissue differentiation. Roles for Notch in carcinogenesis, the biology of cancer stem cells, tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) have been reported. This review describes the role of Notch in the "stemness" program in cancer cells and in metastases, together with a brief update on the Notch inhibitors currently under investigation in oncology. These agents may be useful in targeting cancer stem cells and to reverse the EMT process.
    OncoTargets and Therapy 09/2013; 6:1249-1259. DOI:10.2147/OTT.S36162 · 2.31 Impact Factor
  • Source
    • "Several groups have shown activation of Notch/Jagged in experimental models of renal damage. Interestingly, microarray analysis discloses that Jagged-1 is one of the most highly expressed genes in the experimental model of unilateral ureteral obstruction (UUO) [5], [18], [19]. Previous studies have demonstrated that AngII plays a key role in the pathogenesis of UUO, and pharmacological blockade of AngII (by ACE inhibitors or AT1 receptor antagonists) ameliorates disease progression [38], [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.
    PLoS ONE 07/2012; 7(7):e40490. DOI:10.1371/journal.pone.0040490 · 3.23 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transforming growth factor-β (TGF-β) signaling pathway plays important roles in maintaining normal tissue homeostasis, and is tightly controlled by a network of biomolecules. MicroRNAs (miRNAs) are small noncoding RNAs of ∼22 nucleotides that regulate gene expression at posttranscriptional levels. Increasing evidence points to the important role of miRNAs in TGF-β signaling. OncomicroRNA miR-21 has been established as a key regulator of mesenchymal phenotype transition induced by TGF-β. However, the effects of miR-21 on epithelial biology involved in TGF-β signaling pathway such as cytostatic program and epithelial to mesenchymal transition (EMT) processes are unclear. Here we show that miR-21 is upregulated after TGF-β exposure in both growth inhibition and EMT models of HaCaT keratinocytes. To determine the potential roles of miR-21 in TGF-β-induced growth-arrest and EMT models, we showed that ectopic expression of miR-21 overcame TGF-β' growth-inhibitory effect and the knockdown of miR-21 potentialized this effect, but perturbation of miR-21 levels had little effect on EMT. Moreover, TGFBR2, PTEN, PDCD4, and TAp63 were identified as targets of miR-21 in HaCaT cells. And among them, TGFBR2, PTEN, and TAp63 were associated with TGF-β-induced cytostatic program. Thus, our results suggest that miR-21 regulates the ability of epithelial cells to respond to TGF-β, with potential impact on epithelium homeostasis, wound-healing and tumorigenesis.
    The international journal of biochemistry & cell biology 11/2011; 44(2):366-76. DOI:10.1016/j.biocel.2011.11.012 · 4.05 Impact Factor
Show more

Similar Publications