期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 35, 页码 EB219-EB227出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1722446115
关键词
cell cycle; restriction point; quiescence; G0; CDK2
资金
- NIH [T32 GM 8759-16, S10OD021601, 1K22CA188144-01]
- Boettcher Webb-Waring Early-Career Investigator Award
- Kimmel Scholar Award [SKF16-126]
- Pew-Stewart Scholar for Cancer Research Award
- Searle Scholar Award [SSP-2016-1533]
- Beckman Young Investigator Award
The Restriction Point was originally defined as the moment that cells commit to the cell cycle and was later suggested to coincide with hyperphosphorylation of the retinoblastoma protein (Rb). Current cell cycle models posit that cells exit mitosis into a pre-Restriction Point state, where they have low cyclin-dependent kinase (CDK) activity and hypophosphorylated Rb; passage through the Restriction Point then occurs in late G1. Recent single-cell studies have challenged the current paradigm, raising questions about the location of the Restriction Point and the notion that cells exit mitosis into a pre-Restriction Point state. Here, we use a variety of single-cell techniques to show that both noncancer and cancer cells bifurcate into two subpopulations after anaphase, marked by increasing vs. low CDK2 activity and hyper-vs. hypophosphorylation of Rb. Notably, subpopulations with hyper-and hypophosphorylated Rb are present within minutes after anaphase, delineating one subpopulation that never uncrosses the Restriction Point and continues cycling and another subpopulation that exits mitosis into an uncommitted pre-Restriction Point state. We further show that the CDK inhibitor p21 begins rising in G2 in mother cells whose daughters exit mitosis into the pre-Restriction Point, CDK2(low) state. Furthermore, degradation of p21 coincides with escape from the CDK2(low) state and passage through the Restriction Point. Together, these data support a model in which only a subset of cells returns to a pre-Restriction Point state after mitosis and where the Restriction Point is sensitive to not only mitogens, but also inherited DNA replication stress via p21.
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