Phosphorylation of PPARgamma via Active ERK1/2 Leads to Its Physical Association With p65 and Inhibition of NF-kappabeta

J Cell Biochem. 2003 Nov 1;90(4):732-44. doi: 10.1002/jcb.10668.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • DNA / genetics
  • DNA / metabolism
  • Electrophoretic Mobility Shift Assay
  • Humans
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / chemistry
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Thiazolidinediones / pharmacology
  • Transcription Factor RelA
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • NF-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Thiazolidinediones
  • Transcription Factor RelA
  • Transcription Factors
  • DNA
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • ciglitazone