TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.

Transforming growth factor-β (TGF-β) promotes extracellular matrix deposition by down-regulating the expression of matrix degrading proteinases and upregulating their inhibitors. Tissue inhibitor of metalloproteinases (TIMP)-3 is an ECM-associated specific inhibitor of matrix degrading metalloprotei...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Suvi-Katri Leivonen, Konstantinos Lazaridis, Julie Decock, Andrew Chantry, Dylan R Edwards, Veli-Matti Kähäri
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2d4c950d9b114d0e8632948fbe111271
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2d4c950d9b114d0e8632948fbe111271
record_format	dspace
spelling	oai:doaj.org-article:2d4c950d9b114d0e8632948fbe1112712021-11-18T07:55:31ZTGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.1932-620310.1371/journal.pone.0057474https://doaj.org/article/2d4c950d9b114d0e8632948fbe1112712013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23468994/?tool=EBIhttps://doaj.org/toc/1932-6203Transforming growth factor-β (TGF-β) promotes extracellular matrix deposition by down-regulating the expression of matrix degrading proteinases and upregulating their inhibitors. Tissue inhibitor of metalloproteinases (TIMP)-3 is an ECM-associated specific inhibitor of matrix degrading metalloproteinases. Here, we have characterized the signaling pathways mediating TGF-β-induced expression of TIMP-3. Basal and TGF-β-induced TIMP-3 mRNA expression was abolished in Smad4-deficient mouse embryonic fibroblasts and restoring Smad4 expression rescued the response. Inhibition of Smad signaling by expression of Smad7 and dominant negative Smad3 completely abolished TGF-β-elicited expression of TIMP-3 in human fibroblasts, whereas overexpression of Smad3 enhanced it. Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation with PD98059 and p38 mitogen-activated protein kinase activity by SB203580 resulted in suppression of TGF-β-induced TIMP-3 expression, indicating that ERK1/2 and p38 MAPK mediate the effect of TGF-β on TIMP-3 expression. Specific activation of p38α and ERK1/2 by constitutively active mutants of MKK3b or MEK1, respectively, and simultaneous co-expression of Smad3 resulted in induction of TIMP-3 expression in the absence of TGF-β indicating that Smad3 co-operates with p38 and ERK1/2 in the induction of TIMP-3 expression. These results demonstrate the complex interplay between Smad3, p38α, and ERK1/2 signaling in the regulation of TIMP-3 gene expression in fibroblasts, which may play a role in inflammation, tissue repair, and fibrosis.Suvi-Katri LeivonenKonstantinos LazaridisJulie DecockAndrew ChantryDylan R EdwardsVeli-Matti KähäriPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e57474 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Suvi-Katri Leivonen Konstantinos Lazaridis Julie Decock Andrew Chantry Dylan R Edwards Veli-Matti Kähäri TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.
description	Transforming growth factor-β (TGF-β) promotes extracellular matrix deposition by down-regulating the expression of matrix degrading proteinases and upregulating their inhibitors. Tissue inhibitor of metalloproteinases (TIMP)-3 is an ECM-associated specific inhibitor of matrix degrading metalloproteinases. Here, we have characterized the signaling pathways mediating TGF-β-induced expression of TIMP-3. Basal and TGF-β-induced TIMP-3 mRNA expression was abolished in Smad4-deficient mouse embryonic fibroblasts and restoring Smad4 expression rescued the response. Inhibition of Smad signaling by expression of Smad7 and dominant negative Smad3 completely abolished TGF-β-elicited expression of TIMP-3 in human fibroblasts, whereas overexpression of Smad3 enhanced it. Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation with PD98059 and p38 mitogen-activated protein kinase activity by SB203580 resulted in suppression of TGF-β-induced TIMP-3 expression, indicating that ERK1/2 and p38 MAPK mediate the effect of TGF-β on TIMP-3 expression. Specific activation of p38α and ERK1/2 by constitutively active mutants of MKK3b or MEK1, respectively, and simultaneous co-expression of Smad3 resulted in induction of TIMP-3 expression in the absence of TGF-β indicating that Smad3 co-operates with p38 and ERK1/2 in the induction of TIMP-3 expression. These results demonstrate the complex interplay between Smad3, p38α, and ERK1/2 signaling in the regulation of TIMP-3 gene expression in fibroblasts, which may play a role in inflammation, tissue repair, and fibrosis.
format	article
author	Suvi-Katri Leivonen Konstantinos Lazaridis Julie Decock Andrew Chantry Dylan R Edwards Veli-Matti Kähäri
author_facet	Suvi-Katri Leivonen Konstantinos Lazaridis Julie Decock Andrew Chantry Dylan R Edwards Veli-Matti Kähäri
author_sort	Suvi-Katri Leivonen
title	TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.
title_short	TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.
title_full	TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.
title_fullStr	TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.
title_full_unstemmed	TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.
title_sort	tgf-β-elicited induction of tissue inhibitor of metalloproteinases (timp)-3 expression in fibroblasts involves complex interplay between smad3, p38α, and erk1/2.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/2d4c950d9b114d0e8632948fbe111271
work_keys_str_mv	AT suvikatrileivonen tgfbelicitedinductionoftissueinhibitorofmetalloproteinasestimp3expressioninfibroblastsinvolvescomplexinterplaybetweensmad3p38aanderk12 AT konstantinoslazaridis tgfbelicitedinductionoftissueinhibitorofmetalloproteinasestimp3expressioninfibroblastsinvolvescomplexinterplaybetweensmad3p38aanderk12 AT juliedecock tgfbelicitedinductionoftissueinhibitorofmetalloproteinasestimp3expressioninfibroblastsinvolvescomplexinterplaybetweensmad3p38aanderk12 AT andrewchantry tgfbelicitedinductionoftissueinhibitorofmetalloproteinasestimp3expressioninfibroblastsinvolvescomplexinterplaybetweensmad3p38aanderk12 AT dylanredwards tgfbelicitedinductionoftissueinhibitorofmetalloproteinasestimp3expressioninfibroblastsinvolvescomplexinterplaybetweensmad3p38aanderk12 AT velimattikahari tgfbelicitedinductionoftissueinhibitorofmetalloproteinasestimp3expressioninfibroblastsinvolvescomplexinterplaybetweensmad3p38aanderk12
_version_	1718422719731597312

TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.

Ejemplares similares