Mammalian cells integrate growth factor signals and stress signals in order to make the decision to enter the cell cycle during G1 phase. Cell cycle entry is regulated by activation of the transcription factor E2F, Cyclin Dependent Kinase 2 (CDK2), and inactivation of APC/C. We recently showed that once APC/C inactivates, cells are fully committed to the cell cycle. However, the molecular mechanism underlying irreversible APC/C inactivation was not known. Typically, irreversible switches are mediated by feedback loops, and the kinetics of APC/C inactivation also suggested a feedback loop was involved. We decided to focus on a protein called Early Mitotic Inhibitor 1 (Emi1), which was previously shown to inhibit APC/C activity in S and G2 phase. We found that Emi1 functions as both a substrate of APC/C as well as an inhibitor of APC/C activity, and that Emi1 dynamically switches between these two roles during G1 phase, generating a robust double-negative feedback loop that commits cells to the cell cycle. Furthermore, we uncovered an alternative cell cycle program that allows cells to bypass the requirement for CDK2 and still enter the cell cycle, a finding that has important implications for the development of CDK2 inhibitors for cancer treatments. We plan to study how Emi1 can switch between its two roles as both a substrate and an inhibitor of APC/C to commit cells to the cell cycle, as well as how cells can exploit alternative signaling programs to still proliferate even though essential components have been removed or inhibited.

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National Cancer Institute (NCI)
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Cappell, Steven D; Mark, Kevin G; Garbett, Damien et al. (2018) EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle. Nature 558:313-317