As the name suggests, tumour suppressor genes are genes which code for proteins that are involved in maintaining cellular homeostasis and preventing tumour formation. These genes have different mechanisms of action as shown below, with the principal aim of keeping cells under control. They are crucial in the regulation of the cell cycle, as they prevent division of damaged cells. Some tumour suppressor genes can induce apoptosis of damaged cells while others are able to repair DNA damage. Since tumour suppressor genes are essential in preventing formation of cancerous cells, mutations in these genes increases the risk of many cancers.
Figure 1. The genetic material in our cells is constantly damaged by many factors e.g. UV radiation and free radicals. Cells with damaged DNA may behave abnormally and grow out of control. Luckily our cells have guardians, known as tumour suppressor genes, that check for DNA damage before cells are allowed to divide. When DNA is damaged, tumour suppressor genes cause the expression of candidate genes which stop cell division, repair the damage or induce cell death (apoptosis).
A significant number of tumour suppressor genes have been identified, but the mechanism of action of only a few has been well studied. Scientists also believe that there are still many others that have not been discovered. The most commonly studied tumour suppressor genes are the p53 and retinoblastoma (RB) family members. Both genes prevent damaged cells from dividing by causing cell cycle arrest, using different molecular mechanisms.
Cell cycle arrest
Suppression of the cell cycle is the most commonly used mechanism by tumour suppressor genes. New cells are produced to replace old, damaged cells and as part of the growing process. When cells divide they enter into a highway known as the cell cycle. The body has signals, known as growth factors that tell cells to keep dividing. When enough cells have been produced, these signals are broken down. In order for cells to start dividing, they must go past a checkpoint in the first part of the cell cycle, known as the G1 phase. Both p53 and RB act at this checkpoint to prevent abnormal cells dividing. Cell that go past this checkpoint can go all around the cell cycle and divide. The protein products of p53 and RB only halt division of damaged cells, while normal cells are allowed to divide.
p53 works by checking that the DNA of the cell is correct before it divides. If p53 finds damage in the DNA e.g. a base pair change, then p53 will arrest the cell at the G1 phase and will try to repair the damage. p53 halts cell division by causing the expression of a gene known as p21. The protein product of p21 binds to a protein called cyclin, preventing it to bind to enzymes called cyclin dependent kinases (CDKs). Without cyclin, CDKs have little or no activity, but when cyclin binds to CDKs, they are activated. These enzymes add phosphate groups that act as an on switch, activating substrates involved in promoting cell division. p53 makes sure that CDKs remain inactive by preventing them binding to cyclin, consequently suppressing cell division.
Figure 2. a) If a cell has no DNA damage, p53 will not cause the expression of p21. Cyclin is free and able to bind to CDK which results in its activation. CDK can then activate proteins that allow the cell to go past the G1 checkpoint, allowing cell division. b) However, when p53 detects damage in the cell’s DNA, it induces the expression of a gene called p21. The protein product of p21 binds to cyclin so that CDK remains inactive. p53 will keep the cell at the G1 checkpoint preventing the cell to divide.
The tumour suppressor gene RB expresses the retinoblastoma protein which halts cell division at the G1 phase of the cell cycle, by a slightly different mechanism to p53. RB prevents cells with damaged DNA from dividing. Transcription factors are proteins which cause gene expression and play an important role in the cell cycle, allowing cells to divide. The RB protein functions by binding to transcription factors such as E2F, preventing gene expression and cell division as a result.
Initiation of Apoptosis
Another mechanism used by tumour suppressor genes is that of programmed cell death, also known as apoptosis. Tumour suppressor genes that use this mechanism include p53 and bridging integrator 1 (BIN1). When p53 is unable to repair DNA damage, it will cause the cell to undergo apoptosis. p53 directly activates a protein known as BAX which forms a protein channel in the mitochondria. Pro-apoptotic factors are released through this channel into the cytoplasm where they activate enzymes known as caspases. These enzymes are like the waste disposal system of the cell. Caspases degrade the internal skeleton of the cell and break down the cellular organelles. At the end of apoptosis, the cell breaks into small bits that are taken up by phagocytosis. The whole process is well organised and occurs very quickly.
Figure 3. When DNA damage is irreparable, p53 causes the activation of the protein BAX. This protein is normally found in the cytoplasm, but upon activation by p53 it goes to the mitochondria where it forms a pore known as the bax channel. Pro-apoptotic factors are released from the mitochondria to the cytoplasm through this channel. These factors act to activate caspases such as caspase-9, which induce apoptosis of the cell.
Chemical and UV radiation can induce changes in the DNA inside cells. Tumour suppressor genes such as p53 and BRCA1 can effectively repair small DNA damage, so that the cell does not need to undergo apoptosis. p53 and BRCA1 work together to repair DNA damage by inducing nucleotide excision repair (NER). This DNA repair mechanism essentially involves a pair of biological scissors and some cellular glue. First, a small section of the strand where the damage has occurred is removed from the DNA helix by enzymes known as endonucleases and exonucleases. The gap that is left in the DNA helix is then filled by the help of 2 enzymes: DNA polymerase synthesises the correct bases, while DNA ligase acts like a glue and brings the ends together, joining the strands.
When things go Wrong
Like the brakes in a car are needed in order to stop, tumour suppressor genes halt cells with abnormal DNA from dividing. Mutations in tumour suppressor genes can cause the loss of this cellular ‘break’, allowing abnormal cells to divide uncontrollably. Each gene we have has 2 different versions known as an allele. Most tumour suppressor genes can exert their roles even if one of the alleles is mutated. But they will not be able to produce the correct protein if both alleles are mutated, something known as the ‘two hit hypothesis’. People that have mutations in tumour suppressor genes have an increased risk of developing many different types of cancer during their lifetimes. Women that are born with a BRCA1 mutation carry a lifetime increased risk of breast cancer of 80% and an increased risk of ovarian cancer of 40%.
Certain viruses can lead to cancer by interfering, inhibiting or destroying specific tumour suppressor genes. Polyomavirus influences the regulation of the cell cycle by deregulating the p53 and RB family members. The human papilloma virus (HPV) synthesises an oncogenic (cancer-inducing) protein known as E6 which causes p53 to be degraded by the body in organelles called proteasomes. HPV strains 16 and 18 are responsible for causing 70% of all cervical cancers.
Present and Future
The discovery that many cancers have mutated tumour suppressor genes has helped to further our understandings about the molecular basis of cancer. Now we understand why traditional cancer therapy such as radiotherapy does not always work against some tumours. Radiotherapy is effective at killing cells that divide rapidly e.g. cancer cells, by inducing errors in the DNA, so that p53 induces apoptosis of the cell. However many cancer cells have mutated non-functioning p53, so that the cell does not undergo apoptosis and can continue dividing. Encouraging research is being carried out to develop drugs that can recover the activity of mutated tumour suppressor genes in order to enhance cancer therapy. Further studies and understanding of tumour suppressor genes will provide valuable knowledge to develop better cancer treatments.
Figure 4. Conventional cancer therapy such as radiotherapy targets generic aspects of cancer cells, such as rapid proliferation. Radiotherapy induces irreparable damage to rapidly dividing cells, causing p53 to induce apoptosis. But cancer cells that have p53 mutations that disable its function are more resistant to radiotherapy as they do not undergo apoptosis, which would normally be induced by p53.
Amundson, S.A., Patterson, A., Do, K.T & Fornace Jr, A.J. A nucleotide excision repair master-switch: p53 regulated coordinate induction of global genomic repair genes. Cancer biology & therapy, 1(2), 145-9.
Cox, L.A., Chen, G. & Lee, E.Y. (1994). Tumour suppressor genes and their roles in breast cancer. Breast Cancer Research and Treatment, 32(1), 19-38.
Fridman, J.S. & Lowe, S.W. (2003). Control of apoptosis by p53. Oncogene, 22, 9030-9040.
Lechner, M.S. & Laimins, L.A. inhibition of p53 DNA binding by human papillomavirus E6 proteins. Journal of Virology, 68(7), 4262-4273.
Wanpeng, S. & Yang, J. (2010). Functional Mechanism for Human Tumor Suppressors. Journal of Cancer, 1, 136-140.