Mitogen and Stress Signal Memory Regulates Daughter Cell Proliferation

After the completion of mitosis, daughter cells can enter the next cell cycle immediately or exit to a quiescent state, but it is unknown what drives the selection between proliferative and quiescent states. Yang and colleagues used a live-cell reporter of cyclin-dependent kinase 2 (CDK2) activity to investigate the choice between cell-cycle paths. After mitosis, daughter cells could increase CDK2 activity to proliferate (CDK2^inc), or decrease CDK2 activity to enter a persistent (CDK2^low) or transient (CDK2^delay) quiescent state. MEK inhibition or removal of mitogens in mother cells suppressed cell-cycle entry in daughter cells. ERK activity was elevated in the mother cells of CDK2^inc daughter cells, and ERK signaling promoted cyclin D–CDK4 activity in daughter cells to promote the CDK2^inc path. However, ERK activity was not sufficient to fully predict CDK2 path selection. The DNA damage/p53 signaling pathway was investigated as a potential additional regulatory mechanism, as high levels of p53-regulated p21 are associated with cell-cycle exit. Live-cell analysis of cells with endogenously tagged p53 and p21 revealed that expression of p53 and p21 was higher even before mitosis in cells on the CDK2^low and CDK2^delay paths compared with the CDK2^inc path. This indicates that, along with ERK signaling, DNA damage and p53 signaling in mother cells influence the cell-cycle decision in daughter cells. Further, DNA damage–induced p53 signaling competed with mitogen/ERK signaling in mother cells to determine the CDK2^inc path selection. Stress and mitogen signaling originating in daughter cells then continued to regulate the path selection between CDK2^delay and CDK2^low. Stoichiometric inhibition of cyclin D1–CDK4 activity by p21 resulted in ultrasensitive control of the retinoblastoma and E2F transcriptional programs to determine CDK2 path selection. These findings reveal a mechanism by which daughter cells undergo proliferation or quiescence based on variable mitogen and stress signals in the mother cell, and suggest that mutations affecting the competition between regulators of cyclin D1 and p21 may affect cancer progression.

Yang HW, Chung M, Kudo T, Meyer T. Competing memories of mitogen and p53 signalling control cell-cycle entry. Nature 2017 Sep 6 [Epub ahead of print].

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