Abstract
Precise control of cell proliferation is fundamental to tissue homeostasis and differentiation. Mammalian cells commit to proliferation at the restriction point (R-point). It has long been recognized that the R-point is tightly regulated by the Rb-E2F signaling pathway. Our recent work has further demonstrated that this regulation is mediated by a bistable switch mechanism. Nevertheless, the essential regulatory features in the Rb-E2F pathway that create this switching property have not been defined. Here we analyzed a library of gene circuits comprising all possible link combinations in a simplified Rb-E2F network. We identified a minimal circuit that is able to generate robust, resettable bistability. This minimal circuit contains a feed-forward loop coupled with a mutual-inhibition feedback loop, which forms an AND-gate control of the E2F activation. Underscoring its importance, experimental disruption of this circuit abolishes maintenance of the activated E2F state, supporting its importance for the bistability of the Rb-E2F system. Our findings suggested basic design principles for the robust control of the bistable cell cycle entry at the R-point.
Original language | English (US) |
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Article number | 485 |
Journal | Molecular Systems Biology |
Volume | 7 |
DOIs | |
State | Published - 2011 |
Externally published | Yes |
Keywords
- RbE2F pathway
- bistable switch
- cell cycle checkpoint
- design principle
- robustness
ASJC Scopus subject areas
- Information Systems
- General Biochemistry, Genetics and Molecular Biology
- General Immunology and Microbiology
- General Agricultural and Biological Sciences
- Computational Theory and Mathematics
- Applied Mathematics