Modulation of peroxisome proliferator-activated receptor delta activity affects neural cell adhesion molecule and polysialyltransferase ST8SiaIV induction by teratogenic valproic acid analogs in F9 cell differentiation.
It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferator-activated receptor delta (PPARdelta), and inhibition of histone deacetylases (HDACs). 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 PPARdelta. 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 nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPARdelta but not PPARalpha or PPARgamma in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPARdelta 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 PPARdelta is involved in the signaling pathway.
Lampen
Alfonso
A
Institut für Lebensmitteltoxikologie, Stiftung Tierärztliche Hochschule Hannover, Bischofsholer Damm 15, D-30173 Hannover, Germany. alfonso.lampen@tihohannover.de
Grimaldi
Paul A
PA
Nau
Heinz
H
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012799:Sialyltransferases / Q000096:biosynthesis* / Q000235:genetics; D013723:Teratogens / Q000494:pharmacology*; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D019006:Neural Cell Adhesion Molecules; D047494:PPAR delta; D013723:Teratogens; D014635:Valproic Acid; D012799:Sialyltransferases; C106770:ST8SIA5 protein, human