Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, Rua do Matão 1010, São Paulo 05508-090, SP, Brazil.
Children's Cancer Institute, Porto Alegre, Rio Grande do Sul, Brazil.
Comput Biol Chem. 2023 Oct;106:107926. doi: 10.1016/j.compbiolchem.2023.107926. Epub 2023 Jul 14.
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.
本研究的最终目标是使用布尔网络分析肺腺癌中 FAM111B 和 p53 之间的基因调控。最近的研究表明，FAM111B 的下调增强了相应细胞系中的 G2/M 细胞周期检查点。p53 的上调直接下调 FAM111B，这直接影响细胞周期控制器 Cdc25C 和 CDK1/周期蛋白 B，从而控制 G2/M 细胞周期停滞。至于细胞凋亡，p53 下调 FAM111B 直接调节 BAG3/Bcl-2 轴，触发细胞凋亡。然而，涉及 p53 和 FAM111B 在 G2/M 检查点调控中的分子机制尚不清楚。因此，我们提出了一个考虑 p53 和 FAM111B 影响的 G2/M 检查点布尔模型。我们的模型表明，在 G2/M 检查点，两种细胞表型（阻滞和凋亡）之间的细胞命运是非确定性的，并受 p53 控制。该模型与涉及增益或功能丧失基因的实验数据进行了比较，并且达成了很好的一致性。该模型预测了一个涉及 p53/FAM111B/BAG3 的正回路。我们的电路扰动分析表明，该回路可能对控制 G2/M 检查点的细胞命运决策至关重要。我们的模型支持 FAM111B 是肺腺癌药物开发的一个有吸引力的靶点。
