RT Journal Article
SR Electronic
T1 Induction of Differentiation in F9 Cells and Activation of Peroxisome Proliferator-Activated Receptor δ by Valproic Acid and Its Teratogenic Derivatives
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1269
OP 1276
DO 10.1124/mol.59.5.1269
VO 59
IS 5
A1 Werling, Uwe
A1 Siehler, Sandra
A1 Litfin, Margarethe
A1 Nau, Heinz
A1 Göttlicher, Martin
YR 2001
UL http://molpharm.aspetjournals.org/content/59/5/1269.abstract
AB The antiepileptic drug valproic acid (VPA) is teratogenic, because it induces birth defects in some children of mothers treated for epilepsy. Cellular and molecular actions associated with teratogenicity were identified by testing differentiation of F9 embryocarcinoma cells. VPA altered cell morphology and delayed proliferation. Specific differentiation markers (e.g., c-fos and keratin 18 mRNA and particularly the activating protein-2 transcription factor protein) were induced. This pattern differs from the pattern induced by other teratogens or F9 cell-differentiating agents. Induction of differentiation correlated with teratogenicity because teratogenic derivatives of VPA, such as (S)-4-yn-VPA, induced differentiation, whereas closely related nonteratogenic compounds, such as (R)-4-yn-VPA, 2-en-VPA, and 4-methyl-VPA, did not. In the cellular signaling network, the peroxisome proliferator-activated receptor δ (PPARδ) was activated selectively by VPA and teratogenic derivatives. Depletion of PPARδ by antisense RNA expression precluded the response of F9 cells to VPA. In conclusion, our data show that VPA and its teratogenic derivatives induce a specific type of F9 cell differentiation and that PPARδ is a limiting factor in the control of differentiation.