Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Biophys J. 2011 Nov 2;101(9):2082-91. doi: 10.1016/j.bpj.2011.09.052. Epub 2011 Nov 1.
A kinetic model of a molecular control system for the cellular decision to proliferate or differentiate is formulated and analyzed for the purpose of understanding how the system can break down in cancer cells. The proposed core of this control system is composed of the transcription factors Myc and p53. The network of interactions between these factors involves negative and positive feedback loops that are linked to pathways involved in differentiation, cell cycle, and apoptosis. Understanding the dynamics of the Myc-p53 control system is aided by the postulate that there exists a cancer zone defined as a range of oncogenic Myc activities where the probability of initiating cancer is high. We propose that an essential role of p53 is to prevent the system from entering or staying too long in the cancer zone by downregulating Myc or, when Myc activity somehow becomes too high, by inducing apoptosis, cell cycle arrest, or differentiation. Kinetic modeling illustrates how deletions or aberrations in PTEN, MDM2, and ARF (genes implicated in various cancers, including glioma) affect the Myc-p53 control system. In addition, computer simulations demonstrate how this control system generates different cellular phenotypes characterized by rates of cellular differentiation and proliferation.
为了理解细胞增殖或分化的分子控制系统如何在癌细胞中崩溃，我们建立并分析了该系统的动力学模型。该控制系统的核心由转录因子 Myc 和 p53 组成。这些因子之间的相互作用网络涉及到负反馈和正反馈回路，这些回路与分化、细胞周期和细胞凋亡途径相关。假设存在一个癌症区域，该区域的致癌 Myc 活性范围较高，因此启动癌症的概率也较高，这有助于理解 Myc-p53 控制系统的动态。我们提出，p53 的一个重要作用是通过下调 Myc 或在 Myc 活性过高时通过诱导细胞凋亡、细胞周期停滞或分化来防止系统进入或长时间停留在癌症区域。动力学建模说明了 PTEN、MDM2 和 ARF（涉及各种癌症的基因，包括神经胶质瘤）缺失或异常如何影响 Myc-p53 控制系统。此外，计算机模拟表明，该控制系统如何产生具有不同细胞分化和增殖率的不同细胞表型。
