Mtd/Bok takes a swing: proapoptotic Mtd/Bok regulates trophoblast cell proliferation during human placental development and in preeclampsia

We have previously reported that matador/Bcl-2 ovarian killer (Mtd/Bok), a proapoptotic member of the Bcl-2 family, regulates human trophoblast apoptosis and that its levels are elevated in severe preeclamptic pregnancy. Herein, we show that Mtd is also involved in the regulation of proliferation in normal and pathological placentae. Mtd was found in proliferating trophoblast cells during early placental development and in preeclampsia (PE). The main isoform of Mtd associated with trophoblast proliferation was Mtd-L, the full-length isoform, which preferentially localized to the nuclear compartment in proliferating cells, whereas during apoptosis it switched localization to the cytoplasm where it associated with mitochondria. Mtd expression in proliferating cells colocalized with cyclin E1, a G(1)/S phase cell cycle regulator. MtdL-specific knockdown in the early first trimester villous explants and in HEK293 revealed a direct effect of Mtd-L on cyclin E1 expression and cell cycle progression. We conclude that Mtd-L functions to regulate trophoblast cell proliferation during early placentation and that the elevated levels of Mtd found in PE may contribute to increased trophoblast proliferation accompanying this devastating disorder of pregnancy. Cell Death and Differentiation (2010) 17, 846-859; doi:10.1038/cdd.2009.167; published online 27 November 2009