Mammalian cell cycle entry is controlled at the restriction point by a bistable and resettable switch, which is shown to emerge from a minimal gene circuit containing a mutual-inhibition feedback loop between Rb and E2F modules, coupled with a feed-forward loop between Myc and E2F modules

Bogenmann E

Cheemeng Tan

Guang Yao

Joseph R Nevins

Lingchong You

Mike West

Weinberg RA

Molecular Systems Biology

English

PubMed

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

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Origin of bistability underlying mammalian cell cycle entry

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Robust design of RB–E2F switch GY a oet al 10 Molecular Systems Biology

The kinetic origins of the restriction point in the mammalian cell cycle.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3101952

Origin of bistability underlying mammalian cell cycle entry

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