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TGF-beta1 slows the growth of pathogenic myofibroblasts through a mechanism requiring the focal adhesion protein, Hic-5

TGF-beta1 slows the growth of pathogenic myofibroblasts through a mechanism requiring the focal adhesion protein, Hic-5
TGF-beta1 slows the growth of pathogenic myofibroblasts through a mechanism requiring the focal adhesion protein, Hic-5
Pathogenic scarring is a devastating disorder that impairs normal tissue function after injury. Differentiated myofibroblasts deposit and organize scars over a continuum, from normal to pathogenic, and yet the mechanisms regulating their appearance and disappearance from tissues are enigmatic. We reported previously that key functions of myofibroblasts derived from hypertrophic scars (HTSF) are constitutively activated by an autocrine loop involving transforming growth factor-beta1 (TGF-beta1). We now report that this autocrine induction of TGF-beta1 results in a constitutively high level of Hic-5, which markedly reduces HTSF proliferation relative to normal adult human dermal fibroblasts (NADF) without changing apoptosis. Cyclin D1 and A levels are constitutively lower in HTSF compared to NADF, and the cyclin-dependent kinase inhibitor p21(cip1) is upregulated in HTSF and located in the nucleus. Inhibition of autocrine TGF-beta1 production in HTSF reverses this process, lowering Hic-5 and p21(cip1) levels and increasing replication. Moreover, Hic-5 is partially localized in the nucleus of HTSF, and knocking down Hic-5 with specific siRNAs in these cells results in decreased p21(cip1) levels and a concomitant increase in proliferation. Our findings show that autocrine production of TGF-beta1 upregulates the expression of Hic-5, which is essential for perpetuating the decreased proliferation seen in this pathogenic myofibroblast.
autocrine communication, physiology, cell cycle, cell division, cells, cicatrix, cultured, cyclin a, metabolism, cyclin-dependent kinase inhibitor p21, cyclin-dependent kinase inhibitor p21: metabolism, fibroblasts, pathology, focal adhesions, gene expression, Gene Expression: physiology, Humans, Hypertrophic, Hypertrophic: metabolism, Hypertrophic: pathology, Intracellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins gen, intracellular signaling peptides and proteins met, lim domain p roteins, RNA, skin injuries, small interfering, transforming growth factor beta1
0022-202X
280-291
Dabiri, Ganary
f15211b9-24d5-4770-97dc-19d4d0dd6ec2
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Turner, Christopher E.
a6c1a6bf-91ae-4d92-9980-0534fb696850
Van de Water, Livingston
4e084102-0d09-42d8-9dd0-3464159ddd76
Dabiri, Ganary
f15211b9-24d5-4770-97dc-19d4d0dd6ec2
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Turner, Christopher E.
a6c1a6bf-91ae-4d92-9980-0534fb696850
Van de Water, Livingston
4e084102-0d09-42d8-9dd0-3464159ddd76

Dabiri, Ganary, Tumbarello, David A., Turner, Christopher E. and Van de Water, Livingston (2008) TGF-beta1 slows the growth of pathogenic myofibroblasts through a mechanism requiring the focal adhesion protein, Hic-5. Journal of Investigative Dermatology, 128 (2), 280-291. (doi:10.1038/sj.jid.5700975). (PMID:17671518)

Record type: Article

Abstract

Pathogenic scarring is a devastating disorder that impairs normal tissue function after injury. Differentiated myofibroblasts deposit and organize scars over a continuum, from normal to pathogenic, and yet the mechanisms regulating their appearance and disappearance from tissues are enigmatic. We reported previously that key functions of myofibroblasts derived from hypertrophic scars (HTSF) are constitutively activated by an autocrine loop involving transforming growth factor-beta1 (TGF-beta1). We now report that this autocrine induction of TGF-beta1 results in a constitutively high level of Hic-5, which markedly reduces HTSF proliferation relative to normal adult human dermal fibroblasts (NADF) without changing apoptosis. Cyclin D1 and A levels are constitutively lower in HTSF compared to NADF, and the cyclin-dependent kinase inhibitor p21(cip1) is upregulated in HTSF and located in the nucleus. Inhibition of autocrine TGF-beta1 production in HTSF reverses this process, lowering Hic-5 and p21(cip1) levels and increasing replication. Moreover, Hic-5 is partially localized in the nucleus of HTSF, and knocking down Hic-5 with specific siRNAs in these cells results in decreased p21(cip1) levels and a concomitant increase in proliferation. Our findings show that autocrine production of TGF-beta1 upregulates the expression of Hic-5, which is essential for perpetuating the decreased proliferation seen in this pathogenic myofibroblast.

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More information

e-pub ahead of print date: August 2007
Published date: February 2008
Keywords: autocrine communication, physiology, cell cycle, cell division, cells, cicatrix, cultured, cyclin a, metabolism, cyclin-dependent kinase inhibitor p21, cyclin-dependent kinase inhibitor p21: metabolism, fibroblasts, pathology, focal adhesions, gene expression, Gene Expression: physiology, Humans, Hypertrophic, Hypertrophic: metabolism, Hypertrophic: pathology, Intracellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins gen, intracellular signaling peptides and proteins met, lim domain p roteins, RNA, skin injuries, small interfering, transforming growth factor beta1
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 362400
URI: http://eprints.soton.ac.uk/id/eprint/362400
ISSN: 0022-202X
PURE UUID: 63312447-b610-40ab-83cf-c606bd52103c
ORCID for David A. Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561

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Date deposited: 18 Aug 2014 11:18
Last modified: 09 Jan 2022 03:46

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Contributors

Author: Ganary Dabiri
Author: Christopher E. Turner
Author: Livingston Van de Water

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