Apoptosis induced by atRA in MEPM cells is mediated through activation of caspase and RAR.
We have previously demonstrated that all-trans retinoic (atRA) induced growth inhibition and apoptosis in mouse embryonic palate mesenchymal cells (MEPM). In the present study, we investigated the molecular mechanisms of atRA-induced apoptosis and its putative action pathway. atRA-induced apoptosis is associated with activation of the initiator caspase-9 and the effector caspase-3, but not of the effector caspase-8. A broad caspase inhibitor (z-VAD-fmk), caspase-9 inhibitor z-LEHD-fmk and caspase-3 inhibitor (z-DEVD-fmk) blocked atRA-induced DNA fragmentation and sub-G1 fraction, but not caspase-8 inhibitor z-IETD-fmk. We further showed that atRA dose-dependently promoted mRNA expression of retinoic acid receptor beta (RAR-beta) and gamma. A weaker increase in RAR-alpha mRNA was seen only at the highest concentration of atRA (5 muM). The pan RAR antagonist, BMS493, completely abrogated atRA-induced DNA fragmentation, Sub-G1 fraction, and caspase-3 activation. Taken together, these findings show that caspase-mediated induction of apoptosis by atRA is an RAR-dependent signaling pathway.
Yu
Zengli
Z
School of Stomatology, Peking University Health Science Center, Beijing, China.
Han
Jing
J
Lin
Jiuxiang
J
Xiao
Ying
Y
Zhang
Xingzhong
X
Li
Yong
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010159:Palate / Q000166:cytology / Q000196:embryology; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*
D018168:Receptors, Retinoic Acid; D013723:Teratogens; D014212:Tretinoin; D020169:Caspases