Origin of bistability underlying mammalian cell cycle entry

Guang Yao, Cheemeng Tan, Mike West, Joseph R. Nevins, Lingchong You

Research output: Contribution to journalArticle

73 Citations (Scopus)

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 languageEnglish (US)
Article number485
JournalMolecular Systems Biology
Volume7
DOIs
StatePublished - 2011

Fingerprint

Bistability
Gene Regulatory Networks
Cell Cycle
Cell Cycle Checkpoints
cell cycle
cell proliferation
homeostasis
Homeostasis
Cells
Maintenance
Cell Proliferation
Networks (circuits)
Restriction
Tissue homeostasis
cells
Signaling Pathways
Cell proliferation
Feedback Loop
Robust control
Feedforward

Keywords

  • bistable switch
  • cell cycle checkpoint
  • design principle
  • RbE2F pathway
  • robustness

ASJC Scopus subject areas

  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Computational Theory and Mathematics
  • Information Systems
  • Applied Mathematics

Cite this

Origin of bistability underlying mammalian cell cycle entry. / Yao, Guang; Tan, Cheemeng; West, Mike; Nevins, Joseph R.; You, Lingchong.

In: Molecular Systems Biology, Vol. 7, 485, 2011.

Research output: Contribution to journalArticle

Yao, Guang ; Tan, Cheemeng ; West, Mike ; Nevins, Joseph R. ; You, Lingchong. / Origin of bistability underlying mammalian cell cycle entry. In: Molecular Systems Biology. 2011 ; Vol. 7.
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