title: Induction of cell-cycle arrest by all-trans retinoic acid in mouse embryonic palatal mesenchymal (MEPM) cells.
abstract: 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 maintenance 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 by 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 phase transition. These studies demonstrated that atRA inhibited expression of cyclins D and E at the protein level. Furthermore, atRA treatment reduced phosphorylated Rb and decreased cdk2 and cdk4 kinase activity. These data suggest 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.
authors.affiliation: School of Stomatology, Peking University, Beijing, 100081, China; School of Public Health, Peking University, Beijing, 100083, China.
authors.forename: Zengli
authors.initials: Z
authors.lastname: Yu
authors.forename: Jiuxiang
authors.initials: J
authors.lastname: Lin
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Xingzhong
authors.initials: X
authors.lastname: Zhang
authors.forename: Haichao
authors.initials: H
authors.lastname: Jia
authors.forename: Yunan
authors.initials: Y
authors.lastname: Tang
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D008297:Male; D008648:Mesoderm / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D010159:Palate / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D013723:Teratogens; D014212:Tretinoin; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases