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Reversal of transforming growth factor-β induced epithelial-to-mesenchymal transition and the ZEB proteins.

Das S, Becker BN, Hoffmann FM, Mertz JE - Fibrogenesis Tissue Repair (2012)

Bottom Line: The molecular mechanisms that directly contribute to the re-establishment of the epithelial phenotype are poorly understood.Here, we discuss recent studies from our group and other laboratories identifying signaling pathways leading to the reversal of EMT in fibrotic models.We also present evidence that transcriptional factors such as the ZEB proteins are important regulators for reversal of EMT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

ABSTRACT

Background: The dynamic process of epithelial-to-mesenchymal transition (EMT) is a causal event in kidney fibrosis. This cellular phenotypic transition involves activation of transcriptional responses and remodeling of cellular structures to change cellular function. The molecular mechanisms that directly contribute to the re-establishment of the epithelial phenotype are poorly understood.

Results: Here, we discuss recent studies from our group and other laboratories identifying signaling pathways leading to the reversal of EMT in fibrotic models. We also present evidence that transcriptional factors such as the ZEB proteins are important regulators for reversal of EMT.

Conclusion: These studies provide insights into cellular plasticity and possible targets for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus

Diagram of key events during EMT and MET. TGF-β induces five events for epithelial cells to transition into the mesenchymal state: (i) loss of cell-cell contact, (ii) synthesis of mesenchymal proteins, (iii) re-arrangement of cell structural proteins such as actin, (iv) loss of basement membrane, (iv) loss of apical-basal polarity, and (v) the reverse, mesenchymal to epithelial transition can be induced by cytokines such as BMP-7.
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Figure 1: Diagram of key events during EMT and MET. TGF-β induces five events for epithelial cells to transition into the mesenchymal state: (i) loss of cell-cell contact, (ii) synthesis of mesenchymal proteins, (iii) re-arrangement of cell structural proteins such as actin, (iv) loss of basement membrane, (iv) loss of apical-basal polarity, and (v) the reverse, mesenchymal to epithelial transition can be induced by cytokines such as BMP-7.

Mentions: Our group also examined the effects of ZEB1 and ZEB2 levels during the reversal of EMT Their expression is regulated by TGF-β [13], and they are highly expressed in fetal kidney cells [54]. NMuMG cells, a traditional EMT model [55] where ZEB is highly expressed [44], were incubated with TGF-β1 to induce EMT, and then the five kinase inhibitors targeting TβRI, p38 MAPK, MEK1, JNK, and ROCK were individually added as a reversal agent [40]. We observed that reversal of EMT by the TβRI inhibitor SB431542 involves, in part, inhibiting expression of ZEB1. Further studies demonstrated that depleting mesenchymal cells of ZEB1 and ZEB2 with specific shRNAs was insufficient to restore epithelial-specific protein expression such as E-cadherin [40]. However, targeting ZEB1 and ZEB2 with shRNAs along with adding a ROCK inhibitor led to complete reduction of stress fibers and restoration of epithelial protein expression. Taken together, these data provide evidence that inhibition of the TGF-β pathway regulates the transcriptional expression of epithelial-specific genes via the ZEBs, while other factors such as the Rho kinases are essential to re-establish the epithelial cell structure (Figure 1).


Reversal of transforming growth factor-β induced epithelial-to-mesenchymal transition and the ZEB proteins.

Das S, Becker BN, Hoffmann FM, Mertz JE - Fibrogenesis Tissue Repair (2012)

Diagram of key events during EMT and MET. TGF-β induces five events for epithelial cells to transition into the mesenchymal state: (i) loss of cell-cell contact, (ii) synthesis of mesenchymal proteins, (iii) re-arrangement of cell structural proteins such as actin, (iv) loss of basement membrane, (iv) loss of apical-basal polarity, and (v) the reverse, mesenchymal to epithelial transition can be induced by cytokines such as BMP-7.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368790&req=5

Figure 1: Diagram of key events during EMT and MET. TGF-β induces five events for epithelial cells to transition into the mesenchymal state: (i) loss of cell-cell contact, (ii) synthesis of mesenchymal proteins, (iii) re-arrangement of cell structural proteins such as actin, (iv) loss of basement membrane, (iv) loss of apical-basal polarity, and (v) the reverse, mesenchymal to epithelial transition can be induced by cytokines such as BMP-7.
Mentions: Our group also examined the effects of ZEB1 and ZEB2 levels during the reversal of EMT Their expression is regulated by TGF-β [13], and they are highly expressed in fetal kidney cells [54]. NMuMG cells, a traditional EMT model [55] where ZEB is highly expressed [44], were incubated with TGF-β1 to induce EMT, and then the five kinase inhibitors targeting TβRI, p38 MAPK, MEK1, JNK, and ROCK were individually added as a reversal agent [40]. We observed that reversal of EMT by the TβRI inhibitor SB431542 involves, in part, inhibiting expression of ZEB1. Further studies demonstrated that depleting mesenchymal cells of ZEB1 and ZEB2 with specific shRNAs was insufficient to restore epithelial-specific protein expression such as E-cadherin [40]. However, targeting ZEB1 and ZEB2 with shRNAs along with adding a ROCK inhibitor led to complete reduction of stress fibers and restoration of epithelial protein expression. Taken together, these data provide evidence that inhibition of the TGF-β pathway regulates the transcriptional expression of epithelial-specific genes via the ZEBs, while other factors such as the Rho kinases are essential to re-establish the epithelial cell structure (Figure 1).

Bottom Line: The molecular mechanisms that directly contribute to the re-establishment of the epithelial phenotype are poorly understood.Here, we discuss recent studies from our group and other laboratories identifying signaling pathways leading to the reversal of EMT in fibrotic models.We also present evidence that transcriptional factors such as the ZEB proteins are important regulators for reversal of EMT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

ABSTRACT

Background: The dynamic process of epithelial-to-mesenchymal transition (EMT) is a causal event in kidney fibrosis. This cellular phenotypic transition involves activation of transcriptional responses and remodeling of cellular structures to change cellular function. The molecular mechanisms that directly contribute to the re-establishment of the epithelial phenotype are poorly understood.

Results: Here, we discuss recent studies from our group and other laboratories identifying signaling pathways leading to the reversal of EMT in fibrotic models. We also present evidence that transcriptional factors such as the ZEB proteins are important regulators for reversal of EMT.

Conclusion: These studies provide insights into cellular plasticity and possible targets for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus