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The restriction point is a G₁ phase checkpoint in the cell cycle of animal cells. Prior to the restriction point, a cell exits the cell cycle if specific mitogenic and growth signals are absent. Cells that progress past the restriction point are committed to enter S phase, where DNA synthesis and replication occurs. Yeast cells contain a similar checkpoint, termed the START point.

Discovery of the Restriction Point

In 1974, Arthur Pardee demonstrated that a single restriction point exists for a variety of proliferative and antiproliferative inputs ^[1]. These inputs are integrated in a single switch, termed the restriction point, that regulates the reentry of a cell into a new round of the cell cycle.

Lack of growth factors 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 resulted in inhibition of protein synthesis except in postmitotic cells in the first 3-4 hr of G1 ^[2]. If external conditions are not appropriate for S phase, then the cell may enter G₀ phase, a quiescent stage. Pardee also demonstrated that the restriction point was defective in cancer cell lines, providing physiological relevance for this molecular switch. Mutations in factors contributing to cell cycle arrest at the restriction point are thought to be the main contributors to cancer^[3]

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.

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 back to a quiescent state, and the cell will continue progression through the cell cycle independent of external signals ^[4]. 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

1. ^ Pardee A. Proc. Nat. Acad. Sci. USA Vol. 71, No. 4, pp. 1286-1290, April 1974
2. ^ Zetterberg, A and Larsson, O,: PNAS 1985, 82: 5365-5369.
3. ^ Cancer Cell Cycles, Charles J. Sherr, Science, 6 December 1996
4. ^ Yao G, Lee TJ, Mori S, Nevins JR, You L. Nat Cell Biol. 2008 Apr;10(4):476-82

Cell cycle Interphase G1 phase · S phase · G2 phase M phase Mitosis (Preprophase · Prophase · Prometaphase · Metaphase · Anaphase · Telophase) · Cytokinesis Cell cycle checkpoints Restriction point · Spindle checkpoint · Postreplication checkpoint Other cellular phases Apoptosis · G0 phase · Meiosis