A Dynamical Framework for the All-or-None G1/S Transition.
![Thumbnail](/bitstream/handle/internal/3778/PIIS2405471216000028.pdf.jpg?sequence=26&isAllowed=y)
View/ Open
Date
2016-01-27Author
Barr, AR
Heldt, FS
Zhang, T
Bakal, C
Novák, B
Type
Journal Article
Metadata
Show full item recordAbstract
The transition from G1 into DNA replication (S phase) is an emergent behavior resulting from dynamic and complex interactions between cyclin-dependent kinases (Cdks), Cdk inhibitors (CKIs), and the anaphase-promoting complex/cyclosome (APC/C). Understanding the cellular decision to commit to S phase requires a quantitative description of these interactions. We apply quantitative imaging of single human cells to track the expression of G1/S regulators and use these data to parametrize a stochastic mathematical model of the G1/S transition. We show that a rapid, proteolytic, double-negative feedback loop between Cdk2:Cyclin and the Cdk inhibitor p27(Kip1) drives a switch-like entry into S phase. Furthermore, our model predicts that increasing Emi1 levels throughout S phase are critical in maintaining irreversibility of the G1/S transition, which we validate using Emi1 knockdown and live imaging of G1/S reporters. This work provides insight into the general design principles of the signaling networks governing the temporally abrupt transitions between cell-cycle phases.
Collections
Subject
Humans
Cell Cycle Proteins
G1 Phase
S Phase
Cell Cycle Checkpoints
Anaphase-Promoting Complex-Cyclosome
Research team
Dynamical Cell Systems
Language
eng
Date accepted
2016-01-04
License start date
2016-01-27
Citation
Cell systems, 2016, 2 (1), pp. 27 - 37
Publisher
CELL PRESS