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'{{Refimprove|date=August 2011}} The '''restriction point''' (the “R point”) is an [[animal]] [[cell (biology)|cell]] [[cell cycle checkpoint|checkpoint]] in late [[G1 phase|G₁]] when cells become “committed” to entering the [[cell cycle]]. Prior to the R point, cells are not committed and may enter [[G0 phase|G₀]], or [[quiescence]], if mitogenic signals are absent or counteracted <ref name="pardee73"> Pardee, A.B. A Restriction Point for Control of Normal Animal Cell Proliferation. Proc Natl Acad Sci U S A 71, 1286-1290 (1974)</ref>. After the R point has been passed, cells become irreversibly committed and will proceed through the [[cell cycle]] to [[S phase]], where [[DNA synthesis]] and [[DNA replication|replication]] occurs. This will occur even if extracellular mitogenic signals are removed, demonstrating a shift from extracellular control to intracellular control<ref name="pardee73" /><ref name="pardee89"> Pardee, A.B. G1 events and regulation of cell proliferation. Science 246, 603 (1989)</ref>. [[Yeast]] cells contain a similar checkpoint, termed the [[START point]]. == Discovery of the restriction point == In 1973, [[Arthur Pardee]] demonstrated that a single restriction point exists in [[G1 phase|G₁]]. Previously, [[G1 phase|G₁]] was defined simply as the time between [[mitosis]] and [[S-phase]], and no place-markers for a cell's position in [[G1 phase|G₁]] were known. Pardee used a double-block method in which he shifted cells from one cell cycle block (such as critical amino-acid withdrawal or serum-withdrawal) to another and compared their efficiency at preventing the cells' progression to S-phase. He found that both blocks in all cases examined were equally efficient at blocking S-phase progression, indicating that there is a single block during G₁--the restriction point. Before the R-point, suboptimal extracellular conditions may stop the cell from progressing to S-phase<ref name="pardee73" />. Lack of [[growth factor]]s causes some cells to arrest prior to the restriction point. In 1985, Zetterberg and Larsson discovered that, in all stages of the cell cycle, serum deprivation results in inhibition of protein synthesis except in postmitotic cells in the first 3-4 hours of G1.<ref>{{cite journal |pages=5365–9 |doi=10.1073/pnas.82.16.5365 |title=Kinetic Analysis of Regulatory Events in G1 Leading to Proliferation or Quiescence of Swiss 3T3 Cells |year=1985 |last1=Zetterberg |first1=A. |journal=Proceedings of the National Academy of Sciences |volume=82 |issue=16 |pmid=3860868 |last2=Larsson |first2=O |pmc=390569}}</ref> If external conditions are not appropriate for S phase, the cell may delay until conditions improve (explaining the high variability of G₁ length<ref name="smith">Smith, K.A. Determining to Divide: How Do Cells Decide? Journal of Biological Physics 31, 261-272 (2005).</ref>) or enter [[G0 phase|G₀ phase]], a [[quiescence|quiescent]] stage. After the restriction point has been passed, cells are no longer sensitive to lack of growth factor signaling <ref name="pardee89" /><ref name="smith" /><ref name="lea">Lea, N.C. et al. Commitment Point during G0→G1 That Controls Entry into the Cell Cycle. Molecular and Cellular Biology 23, 2351 -2361 (2003). </ref>, and progression through the cell cycle is regulated by intracellular mechanisms<ref name="hartwell">Hartwell, L.H. & Weinert, T.A. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629 (1989).</ref><ref name="kirschner">1.Murray, A.W. & Kirschner, M.W. Cyclin synthesis drives the early embryonic cell cycle. Nature 339, 275–280 (1989).</ref>. Pardee also demonstrated that the restriction point is defective in cancer cell lines, providing physiological relevance for this molecular switch. [[Mutation]]s in factors contributing to [[cell cycle]] arrest at the restriction point are thought to be the main contributors to [[cancer]].<ref>{{cite journal |pages=1672–7 |doi=10.1126/science.274.5293.1672 |title=Cancer Cell Cycles |year=1996 |last1=Sherr |first1=C. J. |journal=Science |volume=274 |issue=5293 |pmid=8939849}}</ref> == Genes involved in the G1/S transition == The transition from [[G1 phase]] to [[S phase]] involves the phosphorylation and inactivation of the [[retinoblastoma protein]] (Rb), which leads to activation of a positive feedback loop that involves [[E2F]], pRb, and [[cyclin E]]. E2F activates the transcription of several genes involved in DNA replication and S phase progression. [[File:Cell cycle.JPG]] The feedback loop centered on E2F activation exhibits [[bistability]] upon serum stimulation or starvation. Once a threshold level of E2F expression is reached, removal of serum is insufficient to revert to a quiescent state, and the cell will continue progression through the cell cycle independent of external signals.<ref>{{cite journal |pages=476–82 |doi=10.1038/ncb1711 |title=A bistable Rb–E2F switch underlies the restriction point |year=2008 |last1=Yao |first1=Guang |last2=Lee |first2=Tae Jun |last3=Mori |first3=Seiichi |last4=Nevins |first4=Joseph R. |last5=You |first5=Lingchong |journal=Nature Cell Biology |volume=10 |issue=4 |pmid=18364697}}</ref> Rb/Cyclin E/E2F positive feedback is important for driving progression from G1 to S; its involvement in the restriction point has yet to be determined. ==See also== *[[Mitosis]] *[[Start]] *[[Cell cycle]] *[[S-phase-promoting factor]] ==References== {{reflist}} {{Cell cycle}} [[Category:Cell cycle]]'