Cell Cycle Checkpoints

Regulation of the essential processes of the cell cycle, such as DNA replication, chromosome segregation, and mitosis, results from a balance between the functions of growth-promoting genes and growth-suppressing genes. The regulatory proteins work at specific transition points in the cell cycle known as checkpoints.[i]

Feedback from the cell cycle processes and from environmental signals can stop the cell cycle at specific checkpoints, preventing the cell from progressing to the next process before the previous one is completed. These checkpoints protect the cell by sensing conditions that are unfavorable for replication and halting the cell cycle until conditions improve.[i]

Figure 3 illustrates the most prominent checkpoints, including the G₁, G₂, and metaphase checkpoints.[i]

 

It is at the G₁ checkpoint that many cells receive a signal to arrest cell division, halting development at that point. In a continuously cycling cell, the G₁ checkpoint is the point where the control system triggers the initiation of S phase. Regulatory proteins at the G₂ checkpoint trigger entry into the M phase.5

In contrast to the regulatory proteins that promote cellular growth and proliferation, other types of proteins actively inhibit cell cycling. The retinoblastoma (Rb) protein is one such protein. It inhibits cell cycle progression by binding to certain proteins and blocking transcription of genes necessary for progression into S phase. Another important protein that inhibits cell growth and proliferation is p53. Accumulation of the p53 protein responds to DNA damage by halting the cell cycle control system in G₁ or inducing apoptosis.[i]

Growth Factors

Intracellular cell cycle control proteins are not solely responsible for regulation of cell proliferation.[ii]  Normal cells require external growth factors to divide. Other classes of molecules, such as steroid hormones, can also function as growth factors.[iii]

Control of Cell Death

Regulation of cell survival, or cell death, is as important as regulation of cell proliferation to ensuring normal tissue growth and function. In many tissues, cells are programmed to die if they do not receive specific signals for survival. This process of programmed cell death, or apoptosis, is an important part of normal tissue function. Apoptosis is an integral part of many cellular activities, as senescent or damaged cells that are no longer able to carry out their normal functions are eliminated.[iv]

Apoptosis is a natural type of cell death that does not send any aberrant signals to the body, while accidental cell death can lead to signals which can elevate the body’s immune system to activation.  Apoptotic cells usually undergo a characteristic change in which the cell and its nucleus shrink and condense and often fragment (Figure 4). By contrast, cells that die accidentally as a result of acute injury swell and burst in a process called cell necrosis.[v]

Just as with the cell cycle, apoptosis has associated regulatory genes and proteins that ensure normal functioning. When functioning appropriately, apoptosis and cell cycle controls maintain a healthy balance between cell proliferation and cell death that sustains normal tissue function.8 Without appropriate regulation, loss of apoptotic function can lead to an accumulation of cells that can result in cancer development.5

Immunity to Cancer

Cancer cells grow in an uncontrolled manner, invading normal tissues and spreading to distant sites. The immune system employs cell-mediated and humoral defenses to detect and eliminate cancer cell

[i] Novak B, Sible JC, Tyson JJ. Checkpoints in the cell cycle. In: Encyclopedia of Life Sciences. London, UK; Nature Publishing Group. 2002; 1-8.

[ii] Goustin AS, Leof EB, Shipley GD, et al. Growth factors and cancer. Cancer Res. 1986;46:1015-1029.

[iii] Darbre PD, King RJB. Differential effects of steroid hormones on parameters of cell growth. Cancer Res. 1987;47:2937-2944.

[iv] Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut. 2005;54:1024-1033.

[v] Lawen A. Apoptosis-an introduction. BioEssays. 2003;25:888-896.

[vi] Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704-2715.