Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, São Paulo 05508-090, SP, Brazil.
Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, P.O. Box 516, SE-751 20 Uppsala, Sweden.
Cells. 2023 Apr 4;12(7):1085. doi: 10.3390/cells12071085.
Cell fate determination is a complex process that is frequently described as cells traveling on rugged pathways, beginning with DNA damage response (DDR). Tumor protein p53 (p53) and phosphatase and tensin homolog (PTEN) are two critical players in this process. Although both of these proteins are known to be key cell fate regulators, the exact mechanism by which they collaborate in the DDR remains unknown. Thus, we propose a dynamic Boolean network. Our model incorporates experimental data obtained from NSCLC cells and is the first of its kind. Our network's wild-type system shows that DDR activates the G2/M checkpoint, and this triggers a cascade of events, involving p53 and PTEN, that ultimately lead to the four potential phenotypes: cell cycle arrest, senescence, autophagy, and apoptosis (quadra-stable dynamics). The network predictions correspond with the gain-and-loss of function investigations in the additional two cell lines (HeLa and MCF-7). Our findings imply that p53 and PTEN act as molecular switches that activate or deactivate specific pathways to govern cell fate decisions. Thus, our network facilitates the direct investigation of quadruplicate cell fate decisions in DDR. Therefore, we concluded that concurrently controlling PTEN and p53 dynamics may be a viable strategy for enhancing clinical outcomes.
细胞命运决定是一个复杂的过程，常被描述为细胞沿着崎岖的路径行进，从 DNA 损伤反应（DDR）开始。肿瘤蛋白 p53（p53）和磷酸酶和张力蛋白同源物（PTEN）是该过程中的两个关键参与者。尽管这两种蛋白质都被认为是关键的细胞命运调节剂，但它们在 DDR 中协作的确切机制尚不清楚。因此，我们提出了一个动态布尔网络。我们的模型结合了从 NSCLC 细胞中获得的实验数据，这在该领域尚属首次。我们网络的野生型系统表明，DDR 激活 G2/M 检查点，这引发了一连串事件，涉及 p53 和 PTEN，最终导致四种潜在表型：细胞周期停滞、衰老、自噬和凋亡（四稳定动力学）。网络预测与另外两个细胞系（HeLa 和 MCF-7）中的功能获得和丧失研究相吻合。我们的研究结果表明，p53 和 PTEN 作为分子开关，激活或失活特定途径以控制细胞命运决定。因此，我们的网络促进了 DDR 中四重细胞命运决定的直接研究。因此，我们得出结论，同时控制 PTEN 和 p53 的动力学可能是增强临床结果的可行策略。
