scholarly journals Transforming Growth Factor β-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent Growth

2008 ◽  
Vol 28 (22) ◽  
pp. 6889-6902 ◽  
Author(s):  
Amanda C. Daly ◽  
Rebecca A. Randall ◽  
Caroline S. Hill
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Anchorage Independent Growth ◽  
Receptor Complexes ◽  
Morphogenetic Protein ◽  
Growth Inhibitory ◽  
Simultaneous Activation

ABSTRACT Transforming growth factor β (TGF-β) signals predominantly through a receptor complex comprising ALK5 and TβRII to activate receptor-regulated Smads (R-Smads) Smad2 and Smad3. In endothelial cells, however, TGF-β can additionally activate Smad1 and Smad5. Here, we report that TGF-β also strongly induces phosphorylation of Smad1/5 in many different normal epithelial cells, epithelium-derived tumor cells, and fibroblasts. We demonstrate that TβRII and ALK5, as well as ALK2 and/or ALK3, are required for TGF-β-induced Smad1/5 phosphorylation. We show that the simultaneous activation of the R-Smads Smad2/3 and Smad1/5 by TGF-β results in the formation of mixed R-Smad complexes, containing, for example, phosphorylated Smad1 and Smad2. The prevalence of these mixed R-Smad complexes explains why TGF-β-induced Smad1/5 phosphorylation does not result in transcriptional activation via bone morphogenetic protein (BMP)-responsive elements, which bind activated Smad1/5-Smad4 complexes that are induced by BMP stimulation. Thus, TGF-β induces two parallel pathways: one signaling via Smad2-Smad4 or Smad3-Smad4 complexes and the other signaling via mixed R-Smad complexes. Finally, we assess the function of the novel arm of TGF-β signaling and show that TGF-β-induced Smad1/5 activation is not required for the growth-inhibitory effects of TGF-β but is specifically required for TGF-β-induced anchorage-independent growth.

scholarly journals The Intracellular Form of Notch Blocks Transforming Growth Factor β-Mediated Growth Arrest in Mv1Lu Epithelial Cells

2003 ◽  
Vol 23 (18) ◽  
pp. 6694-6701 ◽  
Author(s):  
Prakash Rao ◽  
Tom Kadesch
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Transforming Growth Factor ◽  
Cell Cycle Control ◽  
Transforming Growth Factor Β ◽  
Cell Fate Decisions ◽  
Growth Inhibitory

ABSTRACT Notch signaling influences a variety of cell fate decisions during development, and constitutive activation of the pathway can provoke unbridled cell growth and cancer. The mechanisms by which Notch affects cell growth are not well established. We describe here a novel link between Notch and cell cycle control. We found that Mv1Lu epithelial cells harboring an oncogenic form of Notch (NICD) are resistant to the cell cycle-inhibitory effects of transforming growth factor β (TGF-β). NICD did not affect TGF-β signaling per se but blocked induction of the Cdk inhibitor p15INK4B. c-Myc, whose down-regulation by TGF-β is required for p15INK4B induction, remained elevated in the NICD-expressing cells. c-Myc expression was also maintained in low serum, indicating that Notch's effects on c-Myc are not specific to TGF-β. Our results are consistent with a model in which a strong Notch signal indirectly deregulates c-Myc expression and thereby renders Mv1Lu epithelial cells resistant to growth-inhibitory signals.

Phenol red inhibits growth of renal epithelial cells

1992 ◽  
Vol 262 (4) ◽  
pp. F687-F691 ◽  
Author(s):  
M. M. Walsh-Reitz ◽  
F. G. Toback
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Calf Serum ◽  
Inhibitory Effect ◽  
Phenol Red ◽  
Mitogenic Effect ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory

Phenol red coeluted with a novel kidney cell growth factor during its isolation from conditioned medium by high-performance liquid chromatography. The possibility that phenol red rather than the putative factor mediated the growth-promoting activity was tested, because this pH indicator is known to possess estrogenic properties including a mitogenic effect. Unexpectedly, phenol red at the concentration found in Dulbecco's modified Eagle's medium (DMEM) inhibited growth of monkey (BSC-1) and canine kidney (MDCK) epithelial cells by 20-30%, but stimulated multiplication of 3T3 fibroblasts. The growth-inhibitory effect of phenol red for BSC-1 cells was reversible, concentration dependent, and cell-density independent when multiplication was examined in the presence and absence of the dye. Phenol red partially masked the mitogenic effect of calf serum and epidermal growth factor and was additive to the growth-inhibitory effect of transforming growth factor-beta 2. These observations indicate that phenol red at the concentration in DMEM both underestimates the potency of mitogens and overestimates the strength of an inhibitor of kidney epithelial cell growth and suggest that the dye be omitted from the culture medium when a new growth-regulatory compound is under study.

scholarly journals Transforming growth factor–β in tissue fibrosis

2020 ◽  
Vol 217 (3) ◽  
Author(s):  
Nikolaos G. Frangogiannis
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Cellular Targets ◽  
Extracellular Matrix Molecules ◽  
Interacting Networks

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

Sign in / Sign up

Export Citation Format

Share Document