Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K
Fig 6
Plk1 inhibition at different points along the cell cycle can cause G2 arrest, mitotic catastrophe, aberrant mitosis, or failure of cytokinesis.
(A-D) Top: (A) Molecular mechanism leading to G2 arrest via Plk1 knockdown before the start of prometaphase due to a lack of Cdk1 activation; (B) mitotic catastrophe and apoptosis via Plk1 knockdown in prometaphase or early metaphase due to concurrent Casp2 activation and deactivation of the antiapoptotic BCL2 family; (C) aberrant (premature) anaphase and no cytokinesis via Plk1 knockdown later in metaphase due to premature APC/CCdh1 activation, and (D) normal anaphase but no cytokinesis via Plk1 knockdown post SAC passage due to loss of Plk1H in telophase. Orange/blue background: higher/lower than normal activity; gradient background: premature node transition; no background: other relevant node / process; →: activation; ⊣: inhibition. Bottom: Dynamics of expression / activity of Phase Switch, Cell cycle processes and Apoptotic Switch nodes in cells exposed to Plk1 inhibition at different stages of the cell cycle. X-axis: time-steps; y-axis: nodes of the model organized in modules; orange: ON (expressed and/or active); blue: OFF (not expressed and/or inactive); black: OFF, forcibly inhibited. Black dashed line: timing of Plk1 inhibition; white pathways: processes that initiate apoptosis (B), premature anaphase (C), or failed cytokinesis (D); red box & bar: telophase/G1 in the absence of cytokinesis, followed the next round of DNA synthesis; lime green line: point of normal APC/CCdh1 activation, marking the end of the Plk1 inhibition window that can compromise cytokinesis (D); only relevant module activity is shown (full dynamics available in S1 File).