![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication January 27, 2006.
Revised April 7, 2006.
Accepted for publication April 11, 2006.
and RXR
Represses the TGF
1 Gene via PTEN-Mediated S6K1 Inhibition: Role for Zf9 Dephosphorylation
Peroxisome proliferator-activated receptor-
(PPAR) and retinoic acid X-receptor (RXR) heterodimer regulates cell growth and differentiation. Zf9, whose phosphorylation promotes target genes, is a transcription factor essential for transactivation of the transforming growth factor-
1 (TGF1) gene. This study investigated whether activation of PPAR-RXR heterodimer inhibits TGF1 gene transcription and Zf9 phosphorylation and if so, what signaling pathway regulates it. Either 15-deoxy-
(12,14)-prostaglandin J2 (PGJ2) or 9-cis-retinoic acid (RA) treatment decreased the TGF1 mRNA level in L929 fibroblasts. PGJ2+RA, compared to individual treatment alone, synergistically inhibited the TGF1 gene expression, which was abrogated by PPAR antagonists. Similarly, PGJ2+RA decreased luciferase expression from the TGF1 gene promoter. Promoter deletion analysis of the TGF1 gene revealed that pGL3-323 comprising up to -323 bp region, but lacking PPAR-responsive elements (PPREs), responded to PGJ2+RA. PGJ2+RA treatment inhibited the activity of p70 ribosomal S6 kinase-1 (S6K1), abolishing Zf9 phosphorylation at serine as did rapamycin (an mTOR inhibitor). Zf9 dephosphorylation by PGJ2+RA was reversed by transfection of cells with the plasmid encoding constitutively active S6K1 (CA-S6K1). Transfection with dominant negative S6K1 inhibited the TGF1 gene. Consistently, TGF1 gene repression by PGJ2+RA was antagonized by CA-S6K1. Ectopic expression of PPAR1 and RXR
repressed pGL3-323 transactivation with S6K1 inhibition, which was abrogated by CA-S6K1 transfection. PGJ2+RA induced PTEN, whose overexpression repressed the TGF1 gene through S6K1 inhibition, decreasing ERK1/2-RSK1 and Akt-mTOR phosphorylations. Data indicate that activation of PPAR-RXR heterodimer represses the TGF1 gene and induces Zf9 dephosphorylation via PTEN-mediated S6K1 inhibition, providing insight into pharmacological manipulation of the TGF1 gene regulation.
Key words:
PPARs, Regulation of gene expression
This article has been cited by other articles:
|
|
 |
|
  D. Huang, C. Yang, Y. Wang, Y. Liao, and K. Huang PARP-1 suppresses adiponectin expression through poly(ADP-ribosyl)ation of PPAR{gamma} in cardiac fibroblasts Cardiovasc Res, October 16, 2008; (2008) cvn264v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Lee, S. J. Park, S. R. Kim, K. H. Min, K. Y. Lee, Y. H. Choe, S. H. Hong, Y. R. Lee, J. S. Kim, S. J. Hong, et al. Inhibition of VEGF blocks TGF-{beta}1 production through a PI3K/Akt signalling pathway Eur. Respir. J., March 1, 2008; 31(3): 523 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kratzner, F. Frohlich, K. Lepler, M. Schroder, K. Roher, C. Dickel, M. V. Tzvetkov, T. Quentin, E. Oetjen, and W. Knepel A Peroxisome Proliferator-Activated Receptor {gamma}-Retinoid X Receptor Heterodimer Physically Interacts with the Transcriptional Activator PAX6 to Inhibit Glucagon Gene Transcription Mol. Pharmacol., February 1, 2008; 73(2): 509 - 517. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
