title: Origin of bistability underlying mammalian cell cycle entry.
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.
authors.affiliation: Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ 85721, USA. guangyao@arizona.edu
authors.forename: Guang
authors.initials: G
authors.lastname: Yao
authors.forename: Cheemeng
authors.initials: C
authors.lastname: Tan
authors.forename: Mike
authors.initials: M
authors.lastname: West
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nevins
authors.forename: Lingchong
authors.initials: L
authors.lastname: You
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D053263:Gene Regulatory Networks; D008322:Mammals; D008954:Models, Biological; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein