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Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway

Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway
Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway
Epithelial-mesenchymal transformation (EMT) in response to TGF?1 is a coordinated process of tissue morphogenesis that occurs during embryonic development as well as during certain pathologic events including kidney tubulointerstitial fibrosis. It is characterized by the disassembly of cell–cell junctions and dramatic alterations in the actin cytoskeleton that facilitates cell–matrix adhesion and stimulates migration. The focal adhesion adapter protein, Hic-5, has previously been reported to be upregulated during TGF?1-induced EMT in mouse mammary epithelial cells and the current study recapitulates this result in both mouse kidney proximal tubule epithelial, MCT, cells and human mammary epithelial, MCF10A, cells. To evaluate a causative role for Hic-5 in EMT, Hic-5 RNA interference (siRNA) was used to prevent Hic-5 expression in response to TGF?1 stimulation and was shown to suppress cell migration and actin stress fiber formation. It also resulted in the retention of a robust epithelial cell morphology characterized by elevated E-cadherin protein expression and well-organized adherens junctions. In addition, Hic-5 siRNA treatment led to the suppression of TGF?1 induction of RhoA activation. In contrast, forced expression of Hic-5 led to the formation of ROCK-dependent actin stress fibers. Furthermore, the induction of Hic-5 expression in response to TGF?1 was shown to be a RhoA/ROCK I-dependent process. Together, these data implicate Hic-5 as a key regulator of EMT and suggest that RhoA stimulated Hic-5 expression in response to TGF?1 may be functioning in a feed forward mechanism whereby Hic-5 maintains the mesenchymal phenotype through sustained RhoA activation and signaling.
0021-9541
736-747
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Turner, Christopher E.
a6c1a6bf-91ae-4d92-9980-0534fb696850
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Turner, Christopher E.
a6c1a6bf-91ae-4d92-9980-0534fb696850

Tumbarello, David A. and Turner, Christopher E. (2007) Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway. Journal of Cellular Physiology, 211 (3), 736-747. (doi:10.1002/jcp.20991). (PMID:17299801)

Record type: Article

Abstract

Epithelial-mesenchymal transformation (EMT) in response to TGF?1 is a coordinated process of tissue morphogenesis that occurs during embryonic development as well as during certain pathologic events including kidney tubulointerstitial fibrosis. It is characterized by the disassembly of cell–cell junctions and dramatic alterations in the actin cytoskeleton that facilitates cell–matrix adhesion and stimulates migration. The focal adhesion adapter protein, Hic-5, has previously been reported to be upregulated during TGF?1-induced EMT in mouse mammary epithelial cells and the current study recapitulates this result in both mouse kidney proximal tubule epithelial, MCT, cells and human mammary epithelial, MCF10A, cells. To evaluate a causative role for Hic-5 in EMT, Hic-5 RNA interference (siRNA) was used to prevent Hic-5 expression in response to TGF?1 stimulation and was shown to suppress cell migration and actin stress fiber formation. It also resulted in the retention of a robust epithelial cell morphology characterized by elevated E-cadherin protein expression and well-organized adherens junctions. In addition, Hic-5 siRNA treatment led to the suppression of TGF?1 induction of RhoA activation. In contrast, forced expression of Hic-5 led to the formation of ROCK-dependent actin stress fibers. Furthermore, the induction of Hic-5 expression in response to TGF?1 was shown to be a RhoA/ROCK I-dependent process. Together, these data implicate Hic-5 as a key regulator of EMT and suggest that RhoA stimulated Hic-5 expression in response to TGF?1 may be functioning in a feed forward mechanism whereby Hic-5 maintains the mesenchymal phenotype through sustained RhoA activation and signaling.

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More information

e-pub ahead of print date: 13 February 2007
Published date: June 2007
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 362409
URI: http://eprints.soton.ac.uk/id/eprint/362409
ISSN: 0021-9541
PURE UUID: 562f6806-f47d-46e8-99d1-ec13da1d0a69
ORCID for David A. Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561

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Date deposited: 21 Aug 2014 14:33
Last modified: 03 Dec 2019 01:35

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