Mammalian Ste20-like Protein Kinase 3 Mediates Placental Trophoblast Apoptosis in Physiological and Pathological State

• Main Authors: Wu, Hung-Yi, 吳弘毅
• Other Authors: Yuan, Chiun-Jye
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/14383368932013483698

博士 === 國立交通大學 === 生物科技系所 === 97 === Mammalian Ste20-like protein kinase 3 (Mst3), a novel human Ste20-like serine/threonine protein kinase, plays an important role in the process of cell apoptosis. The labor and preeclampsia caused blood vessels to reduce oxygen supply to induce the oxidative stress and hypoxia, which stimulate the trophoblast apoptosis of placenta. Mst3 was found to be highly expressed in placenta from normal spontaneous delivery or pregnant women complicated with preeclampsia. Mst3 was though to be induced by oxidative stress and hypoxia in the apoptosis of placental trophoblasts. This postulation was confirmed by the observation that the human placental explants treated with oxidative stress or hypoxia exhibited several characteristics, such as Mst3 expression and DNA fragmentation, caspase3 activation, similar to those observed in term placenta and preeclamptic placenta. The role of Mst3 in oxidative stress and hypoxia-induced apoptosis was further demonstrated in the 3A-sub-E, a human trophoblast cell line. The oxidative stress and hypoxia-induced apoptosis of 3A-sub-E could be greatly suppressed by selective knockdown of endogenous Mst3. The results showed that c-Jun N-terminal kinase (JNK) may participate in the signaling pathway of H2O2-induced apoptosis by mediating the level of Mst3. Subsequently, caspase 3 and other downstream apoptotic components may be activated by Mst3 and trigger the apoptotic process in human trophoblasts. The hypoxia-induced Mst3 expression and the apoptosis in human trophoblast were suppressed by the inhibitor of nitric oxide synthase (NOS). NOS activation induces the increase of oxidative stress and then induces Mst3 expression by activating JNK1. Thus, a caspase independent pathway is postulated to be activated by Mst3 and triggers apoptosis of cell. In conclusion, Mst3 may play a role in facilitating fetus spontaneous delivery and pathological preeclampsia.