The ultimate goal of this study is to analyze the gene regulation between FAM111B and p53 in lung adenocarcinoma using Boolean networks. Recent studies have shown that downregulation of FAM111B enhances the G2/M cell cycle checkpoint in the respective cell lines. Upregulation of p53 directly downregulates FAM111B, which is directed to affect cell cycle controllers Cdc25C and Cdk1/CyclinB, thereby controlling G2/M cell cycle arrest. As for apoptosis, down-regulation of FAM111B by p53 directly regulates the BAG3/Bcl-2 axis, which triggers apoptotic cell death. However, the molecular mechanisms involving p53 and FAM111B in G2/M checkpoint regulation are still unknown. Thus, we present a Boolean model of the G2/M checkpoint considering the effect of p53 and FAM111B. Our model indicates that the cell fate between the two cellular phenotypes, arrest, and apoptosis, at the G2/M checkpoint is non-deterministic and is controlled by p53. The model was compared with the experimental data involving gain- or loss-of-function genes and achieved a fair agreement. The model predicts a positive circuit involving p53/FAM111B/BAG3. Our circuit perturbation analysis suggests that this circuit may be essential for controlling cell-fate decisions at the G2/M checkpoint. Our model supports that FAM111B is an engaging target for drug development in lung adenocarcinoma.
Keywords: Apoptosis; BAG 3; Boolean network; Cell cycle arrest; DNA damage; FAM111B; G2/M Checkpoint regulation; Lung adenocarcinoma; P53.
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