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概要：Many biological processes such as tissue repair, immune defense, and cancer progression rely on a vital cellular decision of whether to proliferate or stay in quiescence. Mammalian cells commit to proliferation by triggering a positive feedback whereby the transcription factor E2F activates cyclin-dependent kinase 2 (CDK2), which phosphorylates the E2F inhibitor retinoblastoma (Rb) leading to a further increase in E2F activity to express the genes necessary for proliferation. How cells manage to trigger the positive feedback only when needed is a fundamental question since positive feedbacks can inadvertently amplify small perturbations. We use single-cell analysis of E2F and CDK2 activity dynamics to determine how cells control the positive feedback to safeguard proliferation commitment. Strikingly, cells spend variable times of a few hours to over 20 hours in a reversible state of intermediate E2F activity. The intermediate E2F activity is proportional to the amount of phosphorylation of an evolutionary conserved Threonine 373 (T373) site in Rb. In this seminar, I will discuss a dedicated molecular state of intermediate E2F activation in which cells integrate fluctuating signals to reliably decide whether to disengage or fully engage the positive feedback that flips the Rb-E2F switch and initiates cell proliferation.