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In what way does the ras oncogene contribute to cancers?
The Ras gene codes for a GTPase switch protein that forms part of a growth factor signalling pathway. Stimulation of this protein via a ligand-bound growth factor receptor causes it to activate by exchanging a molecule of GDP for GTP. The activated Ras protein then activates downstream proteins which ultimately activate transcription factors. Normally the Ras signal is self-limiting because the protein has intrinsic GTPase activity, so it hydrolyses its bound GTP to GDP, switching the signal off. There are several known mutations of the Ras gene, but the in best studied example a point mutation of the gene produces a protein with a single amino acid change at the GTP binding site. This severely reduces the protein’s GTPase activity, making it very slow to self-inactivate, once it has been activated. This prolongs the growth signal effectively allowing the cell to be stimulated without a growth factor signal.
What is believed to be a key cause of immortilisation of cancer cells in many tumours?
Reactivation of the telomerase enzyme.
The telomeric DNA protects the chromosome ends from repair enzymes that might otherwise detect them as sites of DNA damage and push the cell into an inappropriate DNA damage response. It is also progressively lost on chromosome replication and, in being sacrificed, protects the ‘real’ chromosomal DNA carrying the genes. In rapidly dividing embryonic cells and stem cells telomerase replenishes the lost telomeric DNA. However, somatic cells do not contain telomerase so that once the telomere is reduced to a critical length cell division ceases. The immortalization of cancer cells has been shown to depend on telomere maintenance. Most, though not all, cancerous cells have been found to have telomerase activity, unlike the normal cells from which they developed.
What is an oncogene?
An oncogene is a mutated form of a normal cellular gene (the proto-oncogene) which codes for a protein which is either controlled abnormally so that it is expressed in abnormally large amounts or has gained activity so that it is more active than the normal protein. In either case only one gene of a pair needs to become oncogenic for the activity to be expressed, so the mutation is dominant. Some oncogenes code for a protein which forms part of a signal transduction pathway. A ‘gain of function’ mutation in such a gene can make the pathway more active. Other oncogenes code for a protein which protects the cell against apoptosis. Increased production of this protein can prevent the cell entering apoptosis. However either of these examples does not give a full definition of an oncogene. Cell cycle control proteins prevent cell division and are anti-oncogenic.
What do tumour-suppressor genes code for?
Tumour-suppressor genes code for proteins that normally control progression through a cell cycle checkpoint. These genes only contribute to a cancer when both copies are mutated in a way that produces an inactive protein product. A single mutation inactivating one gene only has no effect [NO - HAPLOINSUFFECIENCY]. Tumour-suppressor genes contribute to cancer because the absence of the protein product removes controls on cell division. When genes coding for proteins forming part of a growth factor signalling pathway, or coding for proteins which help prevent apoptosis become mutated and contribute to cancers, they become oncogenes. Oncogenes produce proteins that have gained a function. They contribute to cancers by stimulating cell growth, or by preventing a damaged cell from killing itself. Mutations in genes coding for DNA repair enzymes contribute to cancers in the same way that tumour-suppressor genes do, because in their absence damaged DNA cannot be repaired, but they are not conventionally regarded as tumour suppressors.
Which property of p53 enables it to prevent the development of cancer?
The p53 gene is a tumour suppressor gene which is inactivated in at least 50% of all cancers. Its role is to prevent the replication of cells with damaged DNA. p53 protein is normally present at very low levels in the cell, since it is broken down very quickly after its synthesis. However, proteins that recognize lengths of single stranded DNA formed by strand breaks or stalled transcription, phosphorylate p53 and stabilize it, increasing its concentration. p53 protein is a transcription factor, but it causes the production of proteins which halt the cell cycle. It also stimulates production of DNA repair enzymes, but not the ones that replace telomere sequences lost during cell division. The DNA repair enzymes produced give the cell the opportunity to repair its damaged DNA, but if it fails to do so in a reasonable time, p53 protein stimulates production of proteins which push the cell into apoptosis.
What is the role of Rb?
The protein encoded by the retinoblastoma gene (Rb), like p53 also blocks the cycle at the G1 checkpoint. Rb is not itself a transcription factor. It combines with a transcription factor called E2F and prevents E2F from activating genes required for progression into S phase. In normal cells, when a mitogenic stimulus is received, the genes for G1 cyclin synthesis are activated so that the Cdk activity increases. The Cdk phosphorylates and inactivates the Rb protein, preventing it from combining with E2F so that the cycle can advance to S phase. However if the cycle is proceeding in an aberrant way due to an oncogene bypassing the need for a mitogenic signal, since the normally required Cdks are not active, the Rb is not phosphorylated and remains bound to E2F, arresting the cycle. Rb if present and active can therefore restrain the cell cycle from proceeding abnormally. Retinoblastoma gene defects are known to be associated with certain types of cancer.
Malignant vs Benign tumours
Tumours which remain at a single site can usually be dealt with clinically and are therefore regarded as benign. However, even the cells of benign tumours can grow without receiving a growth signal, and can divide indefinitely. A cell mass cannot exceed a diameter of about 2mm unless it develops blood vessels to supply food and oxygen, so benign tumours will also develop blood vessels (angiogenesis). The key point at which a tumour becomes malignant is when cells break free from the initial tumour and spread, via the blood and lymphatic system, to establish themselves in other sites, forming secondary tumours. This is the process of metastasis.
What type of mutation would NOT give rise to an oncogene?
An oncogene is derived from a normal cellular gene (the proto-oncogene) which becomes mutated in such a way that the protein product of the gene is either continuously active or more active than the proto-oncogene product. This is not possible if the product of the mutated gene is an inactive protein.
So the addition or deletion of a base resulting in a nonsense message and an inactive protein product would not give rise to an oncogene.
What can cause the mutations which contribute to the development of cancer?
Carcinogenic (potentially cancer causing) chemicals can be present in some foods. These chemicals may be mutagenic in their native form or be converted to mutagens in the body. Ionising and uv radiation can both cause DNA damage. Reactive oxygen species which are generated in cells from molecular oxygen can also modify DNA, causing mutations. Retroviruses (HIV is a retrovirus with a single stranded RNA genome) are known to introduce mutated genes into cells, contributing to some cancers, and study of this has been important in developing our understanding of cancer and HIV is associated with development of cancers. However, there is no evidence that HIV virus introduces mutations into cells. Its contribution to development of cancers is probably that it suppresses the immune response, making immune surveillance less effective.
How many copies of a tumour suppressor gene need to be inactivated by mutation?
Tumour suppressor genes code for proteins which control progression through cell cycle checkpoints, or which inactivate growth signals. This inhibitory activity can normally take place provided that at least one of a pair of tumour suppressor genes produces an active protein. This is true of the Rb gene, where retinoblastoma, the characteristic cancer produced by inactivation of this gene, only occurs when both copies of the Rb gene are inactivated.
p53 mutations can function as dominant negatives.
