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Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S and S phase cyclin CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2 M DNA damage checkpoint and the spindle checkpoint.

Originally, Howard Martin Temin showed that chicken cells reach a point at which they are committed to replicate their DNA and are not dependent on extracellular signals. About 20 years later, in 1973, Arthur Pardee demonstrated that a single restriction point exists in G1. Previously, G1 had been defined simply as the time between mitosis and S phase. No molecular or morphological place markers for a cell's position in 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 each block's efficiency at preventing progression to S phase. He found that both blocks in all cases examined were equally efficient at blocking S phase progression, indicating that they must all act at the same point in G1, which he termed the "restriction point", or R point. In 1985, Zetterberg and Larsson discovered that, in all stages of the cell cycle, serum deprivation results in inhibition of protein synthesis. Only in postmitotic cells (i. e. cells in early G1) did serum withdrawal force cells into quiescence (G0). In fact, Zetterberg found that virtually all of the variability in cell cycle length can be accounted for in the time it takes the cell to move from the restriction point to S phase.

A paper published by the Lingchong You and Joe Nevins groups at Duke University in 2008 demonstrated that the a bistable hysteric E2F switch underlies the restriction point. E2F promotes its own activation, and also promotes the inhibition of its own inhibitor (pRb), forming two feedback loops (among others) that are important in establishing bistable systems. The authors of this study used a destabilized GFP system under the control of the E2F promoter as a readout of E2F activity. Serum starved cells were stimulated with varying serum concentrations, and the GFP readout was recorded at a single cell level. They found that the GFP reporter was either on or off, indicating that E2F was either completely activated or deactivated at all of the different serum levels analyzed. Further experiments, in which they analyzed the history dependence of the E2F system confirmed that it operates as a hysteretic bistable switch.

Cancer can be seen as a disruption of normal restriction point function, as cells continually and inappropriately reenter the cell cycle, and do not enter G0. Mutations at many steps in the pathway towards the restriction point can result in cancerous growth of cells. Some of the genes most commonly mutated in cancer include Cdks and CKIs; overactive Cdks or underactive CKIs lower the stringency of the restriction point, allowing more cells to bypass senescence. The restriction point is an important consideration in the development of new drug therapies. Under normal physiological conditions, all cell proliferation is regulated by the restriction point. This can be exploited and used as a way to protect non cancerous cells from chemotherapy treatments. Chemotherapy drugs typically attack cells that are proliferating rapidly. By using drugs that inhibit completion of the restriction point, such as growth factor receptor inhibitors, normal cells are prevented from proliferating, and are thus protected from chemotherapy treatments.