期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 41, 页码 E4386-E4393出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1409797111
关键词
tumor heterogeneity; cell dormancy; synthetic uORF; nongenetic cell heterogeneity; positive feedback loop
资金
- NIH [5R21AG040360-02]
- Ellison Medical Foundation [AG-NS-0550-09]
- National Science Foundation Graduate Research Fellowship
- Stanford Graduate Fellowship
- National Institutes of Health (NIH) S10 Shared Instrument Grant [S10RR025518-01]
Phenotypic heterogeneity within a population of genetically identical cells is emerging as a common theme in multiple biological systems, including human cell biology and cancer. Using live-cell imaging, flow cytometry, and kinetic modeling, we showed that two states-quiescence and cell cycling-can coexist within an isogenic population of human cells and resulted from low basal expression levels of p21, a Cyclin-dependent kinase (CDK) inhibitor (CKI). We attribute the p21-dependent heterogeneity in cell cycle activity to double-negative feedback regulation involving CDK2, p21, and E3 ubiquitin ligases. In support of this mechanism, analysis of cells at a point before cell cycle entry (i.e., before the G1/S transition) revealed a p21-CDK2 axis that determines quiescent and cycling cell states. Our findings suggest a mechanistic role for p21 in generating heterogeneity in both normal tissues and tumors.
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