Memory and modularity in cell-fate decision making

摘要

致癌小GTP酶K-Ras发生的突变在癌症中普遍存在，使得这种酶成为一个显然的药物目标，但用小分子直接抑制K-Ras功能却被证明是困难的。在这篇论文中，Shokat及同事报告，它们开发出了能不可逆地与K-Ras的常见G12C突变体结合、但却不与野生型蛋白结合的小分子。晶体研究显示了一个"变构穴"的形成，这在以前的Ras结构中并不明显存在；同时这些小分子也改变K-Ras的亲和性，使其更倾向于与GDP而不是GTP亲和。这些发现应能为以这种突变Ras蛋白为目标的药物发现工作提供一个起点。%Genetically identical cells sharing an environment can display markedly different phenotypes. It is often unclear how much of this variation derives from chance, external signals, or attempts by individual cells to exert autonomous pheno- dissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillus subtilis. We show that the motile state is 'memoryless', exhibiting no autonomous control over the time spent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcing coordination among related cells in the multicellular state. We show that the three-protein regulatory circuit governing the decision is modular, as initiation and maintenance of chaining are genetically separable functions. As stimulation of the same initiating pathway triggers biofilm formation, we argue that autonomous timing allows a trial commitment to multicellularity that external signals could extend.