IFPA Trophoblast Research Award Lecture: the dynamic role of Bcl-2 family members in trophoblast cell fate.

Bcl-2 family members are important regulators of cell fate in normal organ development and in disease status. Pro- and anti-apoptotic members of this family function through a complex network of homo- and hetero-dimers to determine whether a cell lives or dies. Members of the Bcl-2 family are classically recognized for their role in apoptosis, yet emerging evidence has highlighted their importance in the regulation of cell cycle. Cellular proliferation, differentiation and death accompany early placental development of the trophoblast lineage. We have recently reported on the expression and function of two Bcl-2 family members in normal placental development, namely the pro-apoptotic Mtd/Bok, and its anti-apoptotic partner Mcl-1 and have found that their expression is upregulated by low oxygen, a key mediator of trophoblast cell proliferation in early placentation. Interestingly, we have also reported that the expression of the Mtd/Mcl-1 system is altered in preeclampsia, a placental pathology associated with a status of oxidative stress and typically characterized by an immature proliferative trophoblast phenotype and excessive trophoblast cell death. In this pathology levels of pro-apototic Mtd-L and Mtd-P are increased and anti-apoptotic Mcl-1 is cleaved in to a pro-apoptotic isoform. Disruption in Mtd/Mcl-1 expression seen in preeclampsia may contribute to both the increased apoptosis and hyperproliferative nature of this disorder.