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Phosphorylation of PPARγ via active ERK1/2 leads to its physical association with p65 and inhibition of NF‐κβ
Author(s) -
Chen Fei,
Wang Muchun,
O'Connor J. Patrick,
He Mai,
Tripathi Tushar,
Harrison Lawrence E.
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10668
Subject(s) - ciglitazone , peroxisome proliferator activated receptor , phosphorylation , microbiology and biotechnology , signal transduction , chemistry , receptor , kinase , cancer research , biology , biochemistry
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‐κβ 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. © 2003 Wiley‐Liss, Inc.