Aim: 

Bcl-2 family members are key regulators of cell fate in normal organ development and in disease status that are known to function through a complex network of homo- and hetero-dimers to determine whether a cell lives or die. Bcl-2 members are classically recognized for their role in apoptosis, yet emerging evidence has highlighted their importance in the regulation of cell cycle and more recently autophagy. We have 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 altered in preeclampsia, a condition associated with placental hypoxia. Herein we sought to examine the role of Mtd/Mcl-1 system in governing the balance between cell death/autophagy and proliferation in physiological and pathological pregnancies.

Results: 

Mtd/Mcl-1 was found in proliferating trophoblast cells during early placental development and in preeclampsia where it associated with specific cell cycle regulators. Mtd knockdown in villous explants and in HEK293 cells, revealed a direct effect of Mtd on cyclin E1 expression, a G₁/S phase cell cycle regulator. Classical markers of autophagy, including Beclin-1 and LC3, exhibited a unique developmental pattern of expression that inversely correlated to that of Mcl-1. Of clinical relevance we found that preeclampsia displayed altered expression of G1 phase cell cycle regulating molecules as well as increased autophagy and this was associated with altered Mtd/ Mcl-1 levels.

Conclusions: 

Our data suggest that Mtd/Mcl-1 system plays a pivotal role in regulating trophoblast cell fate during physiological pregnancy and that altered Mtd/Mcl-1 rheostat seen in preeclampsia may contribute to both the increased apoptosis/autophagy and hyperproliferative nature of these disorders. (Supported by CIHR and OWH/IGH).