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First published on April 13, 2005; DOI: 10.1124/mol.104.009340

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Received for publication November 16, 2004.
Revised April 13, 2005.
Accepted for publication April 13, 2005.

Modulation of peroxisome proliferator-activated receptor {delta} activity affect NCAM and ST8Sia lV (PST1) induction by teratogenic VPA-analogues in F9 cell differentiation

Alfonso Lampen 1*, Paul A. Grimaldi 2, Heinz Nau 3

1 Institut fur Lebensmitteltoxikologie, Stiftung Tierarztliche Hochschule Hannover, Germany 2 Inserm U636, Centre de Biochimie, University of Nice-Sophia Antipolis, France 3 Institut fur Lebensmitteltoxikologie

* Address correspondence to: E-mail: alfonso.lampen{at}tiho-hannover.de

Abstract

It has been suggested that the teratogenic effects of the antiepilepitic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferator-activated receptor {delta} (PPAR{delta}), and inhibition of histone deacetylases (HDAC). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA-derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPAR{delta}. Treatment of the cells with teratogenic VPA-derivatives or TSA induced differentiation of F9 cells, mRNA and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5' flanking region of the NCAM promoter whereas non-teratogenic VPA-derivatives had no effect at all. The polysialyltransferases (ST8SiaIV [PST1], ST8SiaII) are responsible for the addition of polysialyic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA-derivatives and TSA. As shown by FACS analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA-derivatives. Interestingly, overexpression of the PPAR{delta} but not PPAR{alpha} or PPAR{gamma} in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than mock-transfected F9 cells. Furthermore, repression of PPAR{delta} activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA-compounds or TSA and suggest that in addition to HDAC inhibition PPARd is involved in the signalling pathway.


Key words: PPARs, Promoter analysis, Structure/function/mechanism, Toxicant-induced gene express, Stem cells


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