Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Sci Adv. 2024 Jul 5;10(27):eadm9211. doi: 10.1126/sciadv.adm9211.
Decades ago, mitogen-promoted signaling duration and strength were observed to be sensed by the cell and to be critical for its decisions: to proliferate or differentiate. Landmark publications established the importance of mitogen signaling not only in the G cell cycle phase but also through the S and the G/M transition. Despite these early milestones, how mitogen signal duration and strength, short and strong or weaker and sustained, control cell fate has been largely unheeded. Here, we center on cardinal signaling-related questions, including (i) how fluctuating mitogenic signals are converted into cell proliferation-differentiation decisions and (ii) why extended duration of weak signaling is associated with differentiation, while bursts of strong and short induce proliferation but, if too strong and long, induce irreversible senescence. Our innovative broad outlook harnesses cell biology and protein conformational ensembles, helping us to define signaling strength, clarify cell cycle decisions, and thus cell fate.
几十年前，人们观察到有丝分裂原促进的信号持续时间和强度被细胞感知，这对其决策至关重要：是增殖还是分化。具有里程碑意义的出版物确立了有丝分裂原信号不仅在 G 细胞周期阶段，而且在 S 和 G/M 过渡阶段的重要性。尽管有这些早期的里程碑，但有丝分裂原信号的持续时间和强度（短而强或较弱且持续）如何控制细胞命运在很大程度上仍未得到重视。在这里，我们关注主要的信号相关问题，包括（i）有丝分裂原信号的波动如何转化为细胞增殖-分化决策，以及（ii）为什么延长的弱信号持续时间与分化相关，而强烈和短暂的爆发则诱导增殖，但如果信号过强且过长，则诱导不可逆的衰老。我们的创新广泛视角利用细胞生物学和蛋白质构象集合，帮助我们定义信号强度，阐明细胞周期决策，从而决定细胞命运。
