Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K
Fig 3
Modular Boolean model reproduces the expected quiescent, apoptotic, and cell cycle phenotypes in various extracellular environments.
(A) Stable attractor states of isolated regulatory switches. Blue / light brown / purple / dark red boxes: stable states of the Restriction / Origin of Replication Licensing / Phase / Apoptotic Switch. Orange / blue node border: ON / OFF state. (B) Network representation of the Boolean model partitioned into regulatory switches and processes. Gray: inputs representing environmental factors; green: Growth Signaling; dark red: Apoptotic Switch; light brown: Origin of Replication Licensing Switch; blue: Restriction Switch; purple: Phase Switch; orange: cell cycle processes and molecules that bridge between the multi-stable modules. Black →: activation; red ⊣: inhibition. (C) Cell phenotypes predicted for every combination of no/low/high growth-factor (x axis) and Trail exposure (y axis). The network-wide ON/OFF states of each attractor and the molecular signatures that define their phenotypes are detailed in S2 Table. Blue fragmented cell: apoptotic states (#1–6); gray elongated cell: quiescent/non-dividing states (#7–8); cell with mitotic spindle: cell undergoing repeated cycles (#9). Yellow circle around nucleus: 4N DNA content; double-/single-headed arrows between cells: reversible/ irreversible phenotypic transitions in response to changing environments; green arrow: change in growth factor levels; red: change in Trail exposure. Image credits: apoptotic cell [78]; quiescent cell: https://en.wikipedia.org/wiki/Cell_culture#/media/File:HeLa_cells_stained_with_Hoechst_33258.jpg; mitotic spindle: https://en.wikipedia.org/wiki/Cell_division#/media/File:Kinetochore.jpg.
