Proto-oncogenes

The genes that code for the positive cell-cycle regulators are called proto-oncogenes. Proto-oncogenes are normal genes that, when mutated in certain ways, become oncogenes—genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or non-functional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle; however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to be activated without being partnered with cyclin could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation would not be propagated and no harm would come to the organism. However, if the atypical daughter cells are able to undergo further cell divisions, subsequent generations of cells may accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.

The Cdk gene in the above example is only one of many genes that are considered proto-oncogenes. In addition to the cell-cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell-cycle checkpoints. An oncogene is any gene that, when altered, leads to an increase in the rate of cell-cycle progression.

Tumour Suppressor Genes

Like proto-oncogenes, many of the negative cell-cycle regulatory proteins were discovered in cells that had become cancerous. Tumour suppressor genes are segments of DNA that code for negative regulator proteins, the type of regulators that, when activated, can prevent the cell from undergoing uncontrolled division. The collective function of the best-understood tumour suppressor gene proteins, Rb, p53, and p21, is to put up a roadblock to cell-cycle progression until certain events are completed. A cell that carries a mutated form of a negative regulator might not be able to halt the cell cycle if there is a problem. Tumour suppressors are similar to brakes in a vehicle: Malfunctioning brakes can contribute to a car crash!

Mutated p53 genes have been identified in more than 50 percent of all human tumour cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G₁ checkpoint. A cell with a faulty p53 may fail to detect errors present in the genomic DNA (Figure 4.17). Even if a partially functional p53 does identify the mutations, it may no longer be able to signal the necessary DNA repair enzymes. Either way, damaged DNA will remain uncorrected. At this point, a functional p53 will deem the cell unsalvageable and trigger programmed cell death (apoptosis). The damaged version of p53 found in cancer cells, however, cannot trigger apoptosis.

The role of normal p53 is to monitor DNA and the supply of oxygen (hypoxia is a condition of reduced oxygen supply). If damage is detected, p53 triggers repair mechanisms. If repairs are unsuccessful, p53 signals apoptosis. A cell with an abnormal p53 protein cannot repair damaged DNA and thus cannot signal apoptosis.

The loss of p53 function has other repercussions for the cell cycle. Mutated p53 might lose its ability to trigger p21 production. Without adequate levels of p21, there is no effective block on Cdk activation. Essentially, without a fully functional p53, the G₁ checkpoint is severely compromised and the cell proceeds directly from G₁ to S regardless of internal and external conditions. At the completion of this shortened cell cycle, two daughter cells are produced that have inherited the mutated p53 gene. Given the non-optimal conditions under which the parent cell reproduced, it is likely that the daughter cells will have acquired other mutations in addition to the faulty tumour-suppressor gene. Cells such as these daughter cells quickly accumulate both oncogenes and non-functional tumour-suppressor genes. Again, the result is tumour growth.