萌芽酵母,酿酒酵母,被广泛用作模型生物,用于研究对癌症发展至关重要的真核细胞过程和生长的遗传学,如细胞分裂和细胞周期进程。由于其彻底解决的遗传学,出芽酵母细胞周期也是研究得最好的动力学系统之一。然而,关键细胞周期决定点的基础动力学称为START过渡,细胞进行新一轮的DNA复制和细胞分裂,研究不足。START机制涉及中央细胞周期蛋白依赖性激酶;细胞周期蛋白负责启动过渡,芽的形成,并启动DNA合成;以及它们的转录调节因子。然而,有证据表明,这种机制比简单的不可逆转换开关更复杂。激活关键转录调节子SBF需要其抑制剂的磷酸化,Whi5或SBF/MBF单体组分,Swi6,但不一定两者都有。此外,抑制剂Whi5核出口的时间和机制,虽然重要,对于开始的时间和执行并不重要。因此,需要一个用于出芽酵母START过渡的综合模型,协调监管和空间动态。我们基于已建立的分子相互作用和实验表型,为出芽酵母细胞周期的START转变建立了详细的数学模型(START-BYCC)。START-BYCC概括了潜在的动力学,并正确地模拟了〜150个已知的START突变体的关键表型性状,包括尺寸控制的规定,抑制剂/转录因子复合物的定位,以及营养对尺寸控制的影响。对潜在动力学的这种详细的机械理解使我们更接近去卷积癌症中的异常细胞发育。
Budding yeast, Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5\'s nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ~150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer.