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SHR Neuro Cancer Cardio Lipid Metab Microb
Kocic, J; Bugarski, D; Santibanez, JF.
SMAD3 is essential for transforming growth factor-β1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes.
Eur J Cancer. 2012; 48(10): 1550-1557.
Doi: 10.1016/j.ejca.2011.06.043
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- Abstract:
- Transforming growth factor-β1 (TGF-β1) stimulates the extracellular matrix degrading proteases expression and cell migration in order to enhance cancer cells malignancy. In the present study, we analysed the role of TGF-β1-induced Smad3 activation in the urokinase type plasminogen activator (uPA) production, as well as in cell migration and E-cadherin downregulation in transformed PDV keratinocyte cell line. TGF-β1 signalling was interfered by the chemical inhibitor of the TGF-β1-receptor 1 (ALK5), SB505124, and the specific Smad3 inhibitor, SiS3. Our results showed that TGF-β1 stimulates uPA expression directly through ALK5 activation. The inhibition of Smad3 strongly reduced the capacity of TGF-β1 to stimulate uPA expression, in parallel decreasing the uPA inhibitor plasminogen activator inhibitor type 1 (PAI-1) expression. In addition, the transient expression of dominant negative Smad3 mutant inhibited the TGF-β1-induced uPA promoter transactivation. Moreover, Smad3-/- mouse embryonic fibroblasts were refractory to the induction of uPA by TGF-β1. The inhibition of both ALK5 and Smad3 dramatically blocked the TGF-β1-stimulated E-cadherin downregulation, F-actin reorganisation and migration of PDV cells. Taken together, our results suggest that the TGF-β1-induced activation of Smad3 is the critical step for the uPA upregulation and E-cadherin downregulation, which are the key events preceding the induction of cell migration by TGF-β1 in transformed cells. Copyright © 2011 Elsevier Ltd. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Cadherins - metabolism
- Cell Movement -
- Cells, Cultured -
- Fibroblasts - metabolism
- Gene Expression Regulation -
- Humans -
- Keratinocytes - cytology
- Mice -
- Mice, Transgenic -
- Models, Biological -
- Protein-Serine-Threonine Kinases - metabolism
- Receptor, Transforming Growth Factor-beta Type I -
- Receptors, Transforming Growth Factor beta - metabolism
- Smad3 Protein - genetics
- Smad3 Protein - physiology
- Transforming Growth Factor beta1 - metabolism
- Urokinase-Type Plasminogen Activator - biosynthesis
- Find related publications in this database (Keywords)
- TGF-beta 1
- uPA
- PAI-1
- Smad3
- E-cadherin
- Migration