A Role for Protein Phosphatase 2A in the Proliferation-Quiescence Decision

Abstract

Metazoans precisely control the number of cell divisions during organ or tissue development throughout their lifetime. In adult metazoans, most differentiated cells no longer proliferate and lie in a quiescent state, also termed cell cycle exit. The decision to proliferate or to lie in quiescence is essential for development and its dysregulation may lead to defects in organogenesis, wound healing and regeneration as well as tumor formation. However, at what stage of the cell cycle the proliferation-quiescence decision occurs and what molecular mechanisms control this decision remain controversial. Here my thesis work revealed a novel role for PP2A in promoting the transition to quiescence upon terminal differentiation during tissue development. Using Drosophila eyes and wings as a model, I found that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delayed normal exit. By systematically testing the regulatory subunits of Drosophila PP2A, I discovered that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. In particular, the PP2A/B56 complex targets cyclin-dependent kinase 2 several hours after mitosis to promote entry into quiescence, indicating when the decision occurs and how PP2A impacts the decision. I also investigated the dynamic features of the proliferation-quiescence transition using time-lapse, live imaging in mammalian cell culture. By monitoring the proliferation-quiescence transition without cell synchronization, I discovered that the quiescent state is heterogeneous. Mammalian cells can enter into either a transient or a prolonged quiescent state after mitosis, prior to the next round of cell cycle even under conditions of abundant nutrients. Notably, I showed that two sister cells born of the same mitosis can make different cell cycle decisions, with one cell entering long-term quiescence while the other re-entering the cell cycle. Consistent with my work in the Drosophila model, PP2A in mammals also plays a conserved role in promoting the entry into quiescence. The novel role of PP2A in modulation of the proliferation-quiescence decision may contribute to its tumor suppressor role and impact the emerging problem of tumor dormancy.