Does cell cycle control matter? If you ask an oncologist – a doctor who treats cancer patients – she or he will likely answer with a resounding yes.
Cancer is basically a disease of uncontrolled cell division. Its development and progression are usually linked to a series of changes in the activity of cell cycle regulators. For example, inhibitors of the cell cycle keep cells from dividing when conditions aren’t right, so too little activity of these inhibitors can promote cancer. Similarly, positive regulators of cell division can lead to cancer if they are too active. In most cases, these changes in activity are due to mutations in the genes that encode cell cycle regulator proteins.
Here, we’ll look in more detail at what's wrong with cancer cells. We'll also see how abnormal forms of cell cycle regulators can contribute to cancer.
Cancer cells behave differently than normal cells in the body. Many of these differences are related to cell division behavior.
For example, cancer cells can multiply in culture (outside of the body in a dish) without any growth factors, or growth-stimulating protein signals, being added. This is different from normal cells, which need growth factors to grow in culture.
Cancer cells may make their own growth factors, have growth factor pathways that are stuck in the "on" position, or, in the context of the body, even trick neighboring cells into producing growth factors to sustain them1^11start superscript, 1, end superscript.

Oncogenic form of the Ras protein.
Normal Ras is activated when growth factors bind to growth factor receptors. When active, Ras switches to its GTP-bound form and triggers a signaling pathway leading to cell division and proliferation. Normal Ras then exchanges GTP for GDP and returns to its inactive state until the cell perceives more growth factors.
An oncogenic form of Ras becomes permanently locked in its GTP-bound, active form. The oncogenic Ras protein activates a signaling pathway leading to growth and proliferation even when growth factors are not present.
Many of the proteins that transmit growth factor signals are encoded by proto-oncogenes. Normally, these proteins drive cell cycle progression only when growth factors are available. If one of the proteins becomes overactive due to mutation, however, it may transmit signals even when no growth factor is around. In the diagram above, the growth factor receptor, the Ras protein, and the signaling enzyme Raf are all encoded by proto-oncogenes11^{11}11start superscript, 11, end superscript.
Overactive forms of these proteins are often found in cancer cells. For instance, oncogenic Ras mutations are found in about 90% of pancreatic cancers. Ras is a G protein, meaning that it switches back and forth between an inactive form (bound to the small molecule GDP) and an active form (bound to the similar molecule GTP). Cancer-causing mutations often change Ras’s structure so that it can no longer switch to its inactive form, or can do so only very slowly, leaving the protein stuck in the “on” state (see cartoon above)12^{12}12start superscript, 12, end superscript.
Negative regulators of the cell cycle may be less active (or even nonfunctional) in cancer cells. For instance, a protein that halts cell cycle progression in response to DNA damage may no longer sense damage or trigger a response. Genes that normally block cell cycle progression are known as tumor suppressors. Tumor suppressors prevent the formation of cancerous tumors when they are working correctly, and tumors may form when they mutate so they no longer work. [[How many gene copies must mutate?]](javascript:void(0))
One of the most important tumor suppressors is tumor protein p53, which plays a key role in the cellular response to DNA damage. p53 acts primarily at the G111start subscript, 1, end subscript checkpoint (controlling the G111start subscript, 1, end subscript to S transition), where it blocks cell cycle progression in response to damaged DNA and other unfavorable conditions13^{13}13start superscript, 13, end superscript.
When a cell’s DNA is damaged, a sensor protein activates p53, which halts the cell cycle at the G1_11start subscript, 1, end subscript checkpoint by triggering production of a cell-cycle inhibitor. This pause buys time for DNA repair, which also depends on p53, whose second job is to activate DNA repair enzymes. If the damage is fixed, p53 will release the cell, allowing it to continue through the cell cycle. If the damage is not fixable, p53 will play its third and final role: triggering apoptosis (programmed cell death) so that damaged DNA is not passed on.
![Diagram showing normal p53 and nonfunctional p53.
In response to DNA damage, normal p53 binds DNA and promotes transcription of target genes. First, p53 triggers production of Cdk inhibitor proteins, pausing the cell cycle in G1 to allow time for repairs. p53 also activates DNA repair pathways. Finally, if DNA repair is not possible, p53 triggers apoptosis. The net effect of p53's activities is to prevent the inheritance of damaged DNA, either by getting the damage repaired or by causing the cell to self-destruct.
When a cell contains only nonfunctional p53 that cannot bind DNA, DNA damage can no longer trigger any of these three responses. Although p53 is still activated by the damage, it is helpless to respond, as it can no longer regulate transcription of its targets. Thus, the cell does not pause in G1, DNA damage is not repaired, and apoptosis is not induced. The net effect of the loss of p53 is to permit damaged DNA (mutations) to be passed on to daughter cells.
In response to DNA damage, normal p53 binds DNA and promotes transcription of target genes. First, p53 triggers production of Cdk inhibitor proteins, pausing the cell cycle in G1 to allow time for repairs. p53 also activates DNA repair pathways. Finally, if DNA repair is not possible, p53 triggers apoptosis. The net effect of p53's activities is to prevent the inheritance of damaged DNA, either by getting the damage repaired or by causing the cell to self-destruct.
When a cell contains only nonfunctional p53 that cannot bind DNA, DNA damage can no longer trigger any of these three responses. Although p53 is still activated by the damage, it is helpless to respond, as it can no longer regulate transcription of its targets. Thus, the cell does not pause in G1, DNA damage is not repaired, and apoptosis is not induced. The net effect of the loss of p53 is to permit damaged DNA (mutations) to be passed on to daughter cells.
In cancer cells, p53 is often missing, nonfunctional, or less active than normal. For example, many cancerous tumors have a mutant form of p53 that can no longer bind DNA. Since p53 acts by binding to target genes and activating their transcription, the non-binding mutant protein is unable to do its job14^{14}14start superscript, 14, end superscript.
When p53 is defective, a cell with damaged DNA may proceed with cell division. The daughter cells of such a division are likely to inherit mutations due to the unrepaired DNA of the mother cell. Over generations, cells with faulty p53 tend to accumulate mutations, some of which may turn proto-oncogenes to oncogenes or inactivate other tumor suppressors.
p53 is the gene most commonly mutated in human cancers, and cancer cells without p53 mutations likely inactivate p53 through other mechanisms (e.g., increased activity of the proteins that cause p53 to be recycled)