ToxSci Advance Access published online on November 10, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi030
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 School of Stomatology, Peking University, Beijing, 100081, China
* To whom correspondence should be addressed. All-trans retinoic acid (atRA), the oxidative metabolite of vitamin A, is essential for normal embryonic development. Also, high levels of atRA are teratogenic in many species and can effectively induce cleft palate in the mouse. Most cleft palate resulted from the failed fusion of secondary palate shelves, and maintain of the normal cell proliferation is important in this process of shelf growth. To clarify the mechanism by which atRA causes cleft palate, we investigated the effect of atRA on proliferation activity and cell cycle distribution in mouse embryonic palatal mesenchymal (MEPM) cells. atRA inhibited the growth of MEPM cells with inducing apoptosis in a dose-dependent manner. atRA also caused a G1 block in the cell cycle with an increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S phase as determined by flow cytometry. We next investigated the effects of atRA on molecules that regulate the G1 to S transition. These studies demonstrated that atRA inhibited expression of cyclins D and E at protein level. Furthermore, atRA treatment reduced phosphorylated Rb and decreased cdk2 and cdk4 kinase activity. These data suggested that atRA had antiproliferative activity by modulating G1/S cell cycle regulators and by inhibition of Rb phosphorylation in MEPM cells, which might account for the pathogenesis of cleft palate induced by retinoic acid.
Accepted October 18, 2004
Reproductive and Developmental Toxicology
Induction of Cell-Cycle Arrest by All-Trans Retinoic Acid in Mouse Embryonic Palatal Mesenchymal (MEPM) Cells
2 School of Public Health, Peking University, Beijing, 100083, China
Yong Li, E-mail: liyong{at}bjmu.edu.cn
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