Phosphorylation of PPARγ via Active ERK1/2 Leads to its Physical Association with p65 and Inhibition of NF-κβ

Fei Chen, Muchun Wang, J. Patrick O'Connor, Mai He, Tushar Tripathi, Lawrence Harrison

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptors (PPAR) are novel nuclear receptors and PPARγ ligands have been shown to produce pro-apoptotic effects in many cancer cell types, including colon cancer. PPARγ ligands exert their effect through PPARγ-dependent (genomic) and PPARγ-independent (non-genomic) mechanisms. Recent evidence suggests that PPARγ ligands exert their pro-apoptotic effects in part by directly antagonizing the NF-κβ3 pathway as well as through activation of the MAP kinase pathway. In this report, we have demonstrated that ciglitazone, a member of the thiazoldinedione class of PPARγ ligands induces HT-29 colon cancer cells to undergo apoptosis and prior to apoptosis, ciglitazone exposure results in a transient phosphorylation of PPARγ. This phosphorylation of PPARγ was mediated through the ciglitazone-induced activation of Erk1/2. PPARγ phosphorylation affected the genomic pathway by being inhibitory to PPARγ-DNA binding and PPRE transcriptional activity, as well as the non-genomic pathway by increasing the physical interaction of PPARγ with p65, leading to the inhibition of NF-κβ. Ciglitazone induced phosphorylation of PPARγ through the MAP kinase pathway provides a potential regulatory mechanism for PPARγ′s physical interaction with p65, leading to inhibition of NF-κβ and subsequent apoptosis.

Original languageEnglish (US)
Pages (from-to)732-744
Number of pages13
JournalJournal of Cellular Biochemistry
Volume90
Issue number4
DOIs
StatePublished - Nov 1 2003
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Phosphorylation
Ligands
Apoptosis
Colonic Neoplasms
Phosphotransferases
Chemical activation
Cells
Cytoplasmic and Nuclear Receptors

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Chen, Fei ; Wang, Muchun ; O'Connor, J. Patrick ; He, Mai ; Tripathi, Tushar ; Harrison, Lawrence. / Phosphorylation of PPARγ via Active ERK1/2 Leads to its Physical Association with p65 and Inhibition of NF-κβ. In: Journal of Cellular Biochemistry. 2003 ; Vol. 90, No. 4. pp. 732-744.
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Phosphorylation of PPARγ via Active ERK1/2 Leads to its Physical Association with p65 and Inhibition of NF-κβ. / Chen, Fei; Wang, Muchun; O'Connor, J. Patrick; He, Mai; Tripathi, Tushar; Harrison, Lawrence.

In: Journal of Cellular Biochemistry, Vol. 90, No. 4, 01.11.2003, p. 732-744.

Research output: Contribution to journalArticle

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