A bistable Rb-E2F switch underlies the restriction point.
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.
Yao
Guang
G
Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
Lee
Tae Jun
TJ
Mori
Seiichi
S
Nevins
Joseph R
JR
You
Lingchong
L
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006706:Homeostasis; D008962:Models, Theoretical; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
D003470:Culture Media; D050684:E2F Transcription Factors; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein