The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells

Asish K Ghosh*, Swati Bhattacharyya, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The pleiotropic cytokine transforming growth factor-β (TGF-β) is a potent inducer of collagen synthesis and is implicated in the pathogenesis of fibrosis. Acting in concert with transcriptional coactivators p300/CBP, the Smads mediate TGF-β stimulation of collagen synthesis in human dermal fibroblasts. Little information exists regarding positive and negative modulation of physiological TGF-β responses. Because the tumor suppressor p53 is implicated in connective tissue homeostasis, here we examined the regulation of collagen gene expression by p53. Forced expression of ectopic p53 in dermal fibroblasts repressed basal and TGF-β-stimulated collagen gene expression, whereas the absence of cellular p53 was associated with significantly enhanced transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis. Ectopic expression of p53 also repressed TGF-β stimulation of promoter activity driven by minimal Smad-binding elements, suggesting that p53 modulated Smad-dependent intracellular signaling. Inhibition was not due to altered levels, phosphorylation, or nuclear translocation of cellular Smads. Treatment of fibroblasts with etoposide, a potent inducer of cellular p53, abrogated TGF-β stimulation of COL1A2 promoter activity and collagen synthesis in a p53-dependent manner. Overexpression of the transcriptional coactivator p300 rescued TGF-β stimulation of COL1A2 promoter activity in fibroblasts overexpressing p53. Furthermore, the ligand-induced interaction of cellular Smad3 with p300 or with its cognate Smad-binding DNA element and recruitment of p300 to the DNA-protein complex assembled on the Smad-binding element were markedly reduced in p53-overexpressing fibroblasts. Collectively, these results indicate, for the first time, that p53 is a potent and selective endogenous repressor of TGF-β-regulated collagen gene expression in dermal fibroblasts. The ligand-dependent interaction of Smad3 with p300 may be one of the targets of p53-mediated inhibition of TGF-β responses. These findings suggest that a novel and important physiologic function for the tumor suppressor p53 is the regulation of fibrotic cellular responses.

Original languageEnglish (US)
Pages (from-to)47455-47463
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number46
DOIs
StatePublished - Nov 12 2004

Fingerprint

Transforming Growth Factors
Tumors
Collagen
Genes
Fibroblasts
Neoplasms
Gene expression
Skin
Tissue homeostasis
p300-CBP Transcription Factors
Ligands
Gene Expression
Phosphorylation
DNA
Gene Expression Regulation
Etoposide
Collagen Type I
Connective Tissue
Homeostasis
Fibrosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells",
abstract = "The pleiotropic cytokine transforming growth factor-β (TGF-β) is a potent inducer of collagen synthesis and is implicated in the pathogenesis of fibrosis. Acting in concert with transcriptional coactivators p300/CBP, the Smads mediate TGF-β stimulation of collagen synthesis in human dermal fibroblasts. Little information exists regarding positive and negative modulation of physiological TGF-β responses. Because the tumor suppressor p53 is implicated in connective tissue homeostasis, here we examined the regulation of collagen gene expression by p53. Forced expression of ectopic p53 in dermal fibroblasts repressed basal and TGF-β-stimulated collagen gene expression, whereas the absence of cellular p53 was associated with significantly enhanced transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis. Ectopic expression of p53 also repressed TGF-β stimulation of promoter activity driven by minimal Smad-binding elements, suggesting that p53 modulated Smad-dependent intracellular signaling. Inhibition was not due to altered levels, phosphorylation, or nuclear translocation of cellular Smads. Treatment of fibroblasts with etoposide, a potent inducer of cellular p53, abrogated TGF-β stimulation of COL1A2 promoter activity and collagen synthesis in a p53-dependent manner. Overexpression of the transcriptional coactivator p300 rescued TGF-β stimulation of COL1A2 promoter activity in fibroblasts overexpressing p53. Furthermore, the ligand-induced interaction of cellular Smad3 with p300 or with its cognate Smad-binding DNA element and recruitment of p300 to the DNA-protein complex assembled on the Smad-binding element were markedly reduced in p53-overexpressing fibroblasts. Collectively, these results indicate, for the first time, that p53 is a potent and selective endogenous repressor of TGF-β-regulated collagen gene expression in dermal fibroblasts. The ligand-dependent interaction of Smad3 with p300 may be one of the targets of p53-mediated inhibition of TGF-β responses. These findings suggest that a novel and important physiologic function for the tumor suppressor p53 is the regulation of fibrotic cellular responses.",
author = "Ghosh, {Asish K} and Swati Bhattacharyya and John Varga",
year = "2004",
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T1 - The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells

AU - Ghosh, Asish K

AU - Bhattacharyya, Swati

AU - Varga, John

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Y1 - 2004/11/12

N2 - The pleiotropic cytokine transforming growth factor-β (TGF-β) is a potent inducer of collagen synthesis and is implicated in the pathogenesis of fibrosis. Acting in concert with transcriptional coactivators p300/CBP, the Smads mediate TGF-β stimulation of collagen synthesis in human dermal fibroblasts. Little information exists regarding positive and negative modulation of physiological TGF-β responses. Because the tumor suppressor p53 is implicated in connective tissue homeostasis, here we examined the regulation of collagen gene expression by p53. Forced expression of ectopic p53 in dermal fibroblasts repressed basal and TGF-β-stimulated collagen gene expression, whereas the absence of cellular p53 was associated with significantly enhanced transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis. Ectopic expression of p53 also repressed TGF-β stimulation of promoter activity driven by minimal Smad-binding elements, suggesting that p53 modulated Smad-dependent intracellular signaling. Inhibition was not due to altered levels, phosphorylation, or nuclear translocation of cellular Smads. Treatment of fibroblasts with etoposide, a potent inducer of cellular p53, abrogated TGF-β stimulation of COL1A2 promoter activity and collagen synthesis in a p53-dependent manner. Overexpression of the transcriptional coactivator p300 rescued TGF-β stimulation of COL1A2 promoter activity in fibroblasts overexpressing p53. Furthermore, the ligand-induced interaction of cellular Smad3 with p300 or with its cognate Smad-binding DNA element and recruitment of p300 to the DNA-protein complex assembled on the Smad-binding element were markedly reduced in p53-overexpressing fibroblasts. Collectively, these results indicate, for the first time, that p53 is a potent and selective endogenous repressor of TGF-β-regulated collagen gene expression in dermal fibroblasts. The ligand-dependent interaction of Smad3 with p300 may be one of the targets of p53-mediated inhibition of TGF-β responses. These findings suggest that a novel and important physiologic function for the tumor suppressor p53 is the regulation of fibrotic cellular responses.

AB - The pleiotropic cytokine transforming growth factor-β (TGF-β) is a potent inducer of collagen synthesis and is implicated in the pathogenesis of fibrosis. Acting in concert with transcriptional coactivators p300/CBP, the Smads mediate TGF-β stimulation of collagen synthesis in human dermal fibroblasts. Little information exists regarding positive and negative modulation of physiological TGF-β responses. Because the tumor suppressor p53 is implicated in connective tissue homeostasis, here we examined the regulation of collagen gene expression by p53. Forced expression of ectopic p53 in dermal fibroblasts repressed basal and TGF-β-stimulated collagen gene expression, whereas the absence of cellular p53 was associated with significantly enhanced transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis. Ectopic expression of p53 also repressed TGF-β stimulation of promoter activity driven by minimal Smad-binding elements, suggesting that p53 modulated Smad-dependent intracellular signaling. Inhibition was not due to altered levels, phosphorylation, or nuclear translocation of cellular Smads. Treatment of fibroblasts with etoposide, a potent inducer of cellular p53, abrogated TGF-β stimulation of COL1A2 promoter activity and collagen synthesis in a p53-dependent manner. Overexpression of the transcriptional coactivator p300 rescued TGF-β stimulation of COL1A2 promoter activity in fibroblasts overexpressing p53. Furthermore, the ligand-induced interaction of cellular Smad3 with p300 or with its cognate Smad-binding DNA element and recruitment of p300 to the DNA-protein complex assembled on the Smad-binding element were markedly reduced in p53-overexpressing fibroblasts. Collectively, these results indicate, for the first time, that p53 is a potent and selective endogenous repressor of TGF-β-regulated collagen gene expression in dermal fibroblasts. The ligand-dependent interaction of Smad3 with p300 may be one of the targets of p53-mediated inhibition of TGF-β responses. These findings suggest that a novel and important physiologic function for the tumor suppressor p53 is the regulation of fibrotic cellular responses.

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