Two phases of mitogenic signaling unveil roles for p53 and EGR1 in elimination of inconsistent growth signals. Homo sapiens

Normal cells require continuous exposure to growth factors, in order to cross a restriction point and commit to cell cycle progression. This can be replaced by two short, appropriately spaced pulses of growth factors, where the first pulse primes a process, which is completed by the second pulse, and enables restriction point crossing. Through integration of comprehensive proteomic and transcriptomic analyses of each pulse, we identified three processes that regulate restriction point crossing: (i) The first pulse induces essential metabolic enzymes and activates p53-dependent restraining processes. (ii) The second pulse eliminates, via the PI3K/AKT pathway, the suppressive action of p53, as well as (iii) sets an ERK-EGR1 threshold mechanism, which digitizes graded external signals into an all-or-none decision obligatory for S-phase entry. Together, our findings uncover novel gating mechanisms, which ensure that cells ignore fortuitous growth factors, and undergo proliferation only in response to consistent mitogenic signals. Overall design: 17 samples; one control sample, time zero.

正常细胞需要持续暴露于生长因子（growth factors），方可越过限制点并启动细胞周期进程。该过程可通过两次间隔适当的短时长生长因子脉冲替代：第一次脉冲启动相关进程，第二次脉冲完成该进程并使细胞得以越过限制点。通过对两次脉冲分别开展全面的蛋白质组学（proteomics）与转录组学（transcriptomics）整合分析，我们鉴定出三种调控限制点跨越的过程：(i) 第一次脉冲诱导关键代谢酶并激活p53依赖的抑制过程；(ii) 第二次脉冲通过PI3K/AKT通路消除p53的抑制作用；以及(iii) 建立ERK-EGR1阈值机制，该机制可将分级的外部信号转化为进入S期所必需的“全有或全无”决策。综上，我们的发现揭示了全新的门控机制，可确保细胞忽略偶然出现的生长因子，仅在响应持续的有丝分裂原信号时才启动增殖。实验整体设计：共包含17个样本，其中1个为零时刻对照样本。