All-trans retinoic acid induces TGF-β<inf>2</inf> in intestinal epithelial cells via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2

Kopperuncholan Namachivayam, Krishnan MohanKumar, Dima Arbach, Ramasamy Jagadeeswaran, Sunil Jain, Viswanathan Natarajan, Dolly Mehta, Robert P. Jankov, Akhil Maheshwari

Research output: Contribution to journalArticle

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Abstract

Objective We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks' gestation, because of the developmental deficiency of transforming growth factor (TGF)-β<inf>2</inf> in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β<inf>2</inf> in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. Methods AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β<inf>2</inf> expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RTqPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently- transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. Results AtRA-treatment of IEC6 cells selectively increased TGF-β<inf>2</inf> mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β<inf>2</inf> promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β<inf>2</inf> promoter and increased histone H2B acetylation in the TGF-β<inf>2</inf> nucleosome, which is typically associated with transcriptional activation. Conclusions AtRA induces TGF-β<inf>2</inf> expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation.

Original languageEnglish (US)
Article number134003
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 30 2015

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Activating Transcription Factor 2
transforming growth factors
retinoic acid
Transforming Growth Factors
p38 Mitogen-Activated Protein Kinases
Tretinoin
mitogen-activated protein kinase
epithelial cells
transcription factors
Epithelial Cells
Chemical activation
Western blotting
Western Blotting
promoter regions
Protective Agents
enterocolitis
Acetylation
rho-Associated Kinases
Necrotizing Enterocolitis
nucleosomes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

All-trans retinoic acid induces TGF-β<inf>2</inf> in intestinal epithelial cells via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. / Namachivayam, Kopperuncholan; MohanKumar, Krishnan; Arbach, Dima; Jagadeeswaran, Ramasamy; Jain, Sunil; Natarajan, Viswanathan; Mehta, Dolly; Jankov, Robert P.; Maheshwari, Akhil.

In: PLoS One, Vol. 10, No. 7, 134003, 30.07.2015.

Research output: Contribution to journalArticle

Namachivayam, K, MohanKumar, K, Arbach, D, Jagadeeswaran, R, Jain, S, Natarajan, V, Mehta, D, Jankov, RP & Maheshwari, A 2015, 'All-trans retinoic acid induces TGF-β<inf>2</inf> in intestinal epithelial cells via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2', PLoS One, vol. 10, no. 7, 134003. https://doi.org/10.1371/journal.pone.0134003
Namachivayam, Kopperuncholan ; MohanKumar, Krishnan ; Arbach, Dima ; Jagadeeswaran, Ramasamy ; Jain, Sunil ; Natarajan, Viswanathan ; Mehta, Dolly ; Jankov, Robert P. ; Maheshwari, Akhil. / All-trans retinoic acid induces TGF-β<inf>2</inf> in intestinal epithelial cells via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. In: PLoS One. 2015 ; Vol. 10, No. 7.
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abstract = "Objective We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks' gestation, because of the developmental deficiency of transforming growth factor (TGF)-β2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. Methods AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RTqPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently- transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. Results AtRA-treatment of IEC6 cells selectively increased TGF-β2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β2 promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β2 promoter and increased histone H2B acetylation in the TGF-β2 nucleosome, which is typically associated with transcriptional activation. Conclusions AtRA induces TGF-β2 expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation.",
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AU - Namachivayam, Kopperuncholan

AU - MohanKumar, Krishnan

AU - Arbach, Dima

AU - Jagadeeswaran, Ramasamy

AU - Jain, Sunil

AU - Natarajan, Viswanathan

AU - Mehta, Dolly

AU - Jankov, Robert P.

AU - Maheshwari, Akhil

PY - 2015/7/30

Y1 - 2015/7/30

N2 - Objective We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks' gestation, because of the developmental deficiency of transforming growth factor (TGF)-β2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. Methods AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RTqPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently- transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. Results AtRA-treatment of IEC6 cells selectively increased TGF-β2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β2 promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β2 promoter and increased histone H2B acetylation in the TGF-β2 nucleosome, which is typically associated with transcriptional activation. Conclusions AtRA induces TGF-β2 expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation.

AB - Objective We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks' gestation, because of the developmental deficiency of transforming growth factor (TGF)-β2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. Methods AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RTqPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently- transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. Results AtRA-treatment of IEC6 cells selectively increased TGF-β2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β2 promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β2 promoter and increased histone H2B acetylation in the TGF-β2 nucleosome, which is typically associated with transcriptional activation. Conclusions AtRA induces TGF-β2 expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation.

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