Nfatc1 regulation of trail expression in human intestinal cells

Qingding Wang, Yuning Zhou, Heidi L. Weiss, Chi Wing Chow, B. Mark Evers

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter.

Original languageEnglish (US)
Article numbere19882
JournalPLoS One
Volume6
Issue number5
DOIs
StatePublished - 2011

Fingerprint

NFATC Transcription Factors
T-lymphocytes
TNF-Related Apoptosis-Inducing Ligand
promoter regions
Chemical activation
cells
Acetates
protein synthesis
acetates
Sp1 Transcription Factor
Cell signaling
cyclosporine
Calcium Ionophores
Calcimycin
ionophores
RNA Interference
RNA interference
cell differentiation
Cyclosporine
Cell Differentiation

ASJC Scopus subject areas

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

Cite this

Wang, Q., Zhou, Y., Weiss, H. L., Chow, C. W., & Evers, B. M. (2011). Nfatc1 regulation of trail expression in human intestinal cells. PLoS One, 6(5), [e19882]. https://doi.org/10.1371/journal.pone.0019882

Nfatc1 regulation of trail expression in human intestinal cells. / Wang, Qingding; Zhou, Yuning; Weiss, Heidi L.; Chow, Chi Wing; Evers, B. Mark.

In: PLoS One, Vol. 6, No. 5, e19882, 2011.

Research output: Contribution to journalArticle

Wang, Q, Zhou, Y, Weiss, HL, Chow, CW & Evers, BM 2011, 'Nfatc1 regulation of trail expression in human intestinal cells', PLoS One, vol. 6, no. 5, e19882. https://doi.org/10.1371/journal.pone.0019882
Wang, Qingding ; Zhou, Yuning ; Weiss, Heidi L. ; Chow, Chi Wing ; Evers, B. Mark. / Nfatc1 regulation of trail expression in human intestinal cells. In: PLoS One. 2011 ; Vol. 6, No. 5.
@article{3246b5c18d3246b9b188b274c2234454,
title = "Nfatc1 regulation of trail expression in human intestinal cells",
abstract = "TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter.",
author = "Qingding Wang and Yuning Zhou and Weiss, {Heidi L.} and Chow, {Chi Wing} and Evers, {B. Mark}",
year = "2011",
doi = "10.1371/journal.pone.0019882",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Nfatc1 regulation of trail expression in human intestinal cells

AU - Wang, Qingding

AU - Zhou, Yuning

AU - Weiss, Heidi L.

AU - Chow, Chi Wing

AU - Evers, B. Mark

PY - 2011

Y1 - 2011

N2 - TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter.

AB - TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter.

UR - http://www.scopus.com/inward/record.url?scp=79956114443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79956114443&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0019882

DO - 10.1371/journal.pone.0019882

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e19882

ER -