A bistable Rb–E2F switch underlies the restriction point
- 23 March 2008
- journal article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 10 (4), 476-482
- https://doi.org/10.1038/ncb1711
Abstract
The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that the Rb-E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses. Once turned ON by sufficient serum stimulation, E2F can memorize and maintain this ON state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point.Keywords
This publication has 30 references indexed in Scilit:
- The E2F family: specific functions and overlapping interestsThe EMBO Journal, 2004
- Molecular mechanisms of E2F-dependent activation and pRB-mediated repressionJournal of Cell Science, 2004
- A positive-feedback-based bistable ‘memory module’ that governs a cell fate decisionNature, 2003
- Hysteresis drives cell-cycle transitions in Xenopus laevis egg extractsProceedings of the National Academy of Sciences of the United States of America, 2002
- Signaling Networks That Link Cell Proliferation and Cell FatePublished by Elsevier BV ,2002
- To cycle or not to cycle: a critical decision in cancerNature Reviews Cancer, 2001
- CDK inhibitors: positive and negative regulators of G1-phase progressionGenes & Development, 1999
- What is the restriction point?Current Opinion in Cell Biology, 1995
- Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells.Proceedings of the National Academy of Sciences of the United States of America, 1985
- A Restriction Point for Control of Normal Animal Cell ProliferationProceedings of the National Academy of Sciences of the United States of America, 1974