The word oncogene is perhaps one of the more confusing terms in medical biology. The name indicates a gene that causes cancer, with the implication that these genes exist primarily for the purpose of creating tumours. In fact, the normal role of many of the genes which are designated as oncogenes is to regulate cell growth or cell death and to protect the cell against transformation into a neoplastic cell. In this sense they are anti-oncogenes by their true nature.

Observations on eytmology aside, two types of oncogenes exist. One form actively assists in the development of neoplasia once it is mutated in a particular way; the name oncogene is now commonly reserved for these mutated genes that actively encourage neoplasia. The other type is the tumour suppressor gene. Tumour suppressor genes protect the cell against neoplasia but if they become defective due to mutation they lose this ability.

One problem with much of the work that has been done on oncogenes is that the proteins which have been described are usually concerned with cell division or repairing DNA damage. A malignant cell requires assorted other properties beyond autonomous growth and elucidation of which genes confer properties such as invasion and metastasis seems to be somewhat neglected by comparison. Even standard schemes of the sequences of mutations that characteristically occur in certain tumours often overlook the fact that none of these mutations will intrinsically endow the cell with invasive or metastatic capabilities.


Numerous sorts of oncogenes exist. Some are specific to one or a few cancers, others are common to many. They are frequently connected with the stimulation and regulation of cell division. If the normal gene (referred to as a proto-oncogene, as if its sole function is to sit around twiddling its thumbs waiting to be mutated into an oncogene), suffers a particular mutation, the activity of the protein it encodes can become unregulated. Thus, a protein that only signals the cell to divide under specific circumstances is converted into one which provides a constant signal to the cell to proliferate.

Rather than driving cell into unregulated division an oncogene can instead confer a growth advantage on a cell by protecting it against apoptosis. Some tumour suppressor genes operate by inducing mutated cells to commit apoptosis before they can reproduce. If the cell has neutralised its apoptosis system then it is protected against this mechanism. T cells can also target mutated cells and trigger apoptosis, so anti-apoptotic ability also defends the neoplastic cells against this attack.

Specific Examples

The ras family of proteins is a type of a signalling protein. The ras proteins are G proteins. G proteins are involved in assorted signalling pathways. They are attached to cell surface receptors. When the appropriate molecule binds to the receptor this activates the G protein by the binding of GTP (guanosine triphosphate) to the G protein. As long as GTP is bound the G protein can then interact with its target protein and modify the function of the target (usually by activating it). In order to limit the duration of action of the G protein relayed signal, the G protein has intrinsic GTPase activity. This GTPase ability allows the G protein to convert the GTP to GDP (guanosine diphosphate), thereby returning the G protein to its dormant state until it receives the relevant signal again. Certain mutations of the ras gene abolish or reduce the GTPase activity of the G protein and therefore make it hyperactive. As a result the signal it delivers to the cell is excessive. The ras G proteins convey signals regarding cell division and thus mutations in the ras gene result in inappropriate stimulation of cell division.

External signals that instruct the cell to divide can also be transmitted to the nucleus by tyrosine kinase linked receptors. Like G proteins the ligand for these receptors is sometimes a growth factor. Tyrosine kinases work by phosphorylating tyrosine residues on their target protein. This phosphorylation activates the target and thus engages the next step in the signalling pathway. The kinase activity is short-lived and self deactivates, thus limiting the signal. However, if the tyrosine kinase suffers a mutation that causes it to become permanently active it will transmit a strong, continuous signal to the cell nucleus to divide. The c-kit gene codes a tyrosine kinase receptor that is expressed on haematopoietic stem cells. In chronic myeloid leukaemia the c-kit gene is mutated and its activity becomes independent of binding the necessary growth factor.

Intracellular proteins are also crucial in the regulation of cell proliferation and either drive the cell through its proliferative cycle or serve as inhibitors of cell division that must be overcome before the cell can divide. The former group include the family of cyclin enzymes and their target proteins, the cyclin dependent kinases. Mantle cell lymphoma features a translocation of the cyclin D1 gene that places the encoding region of the cyclin D1 gene (chromosome 14q32) under the control of the promoter region of the immunoglobulin heavy chain gene (chromosome 11q13) in the abnormal B lymphocyte. B cells normally express abundant immunoglobulin so the heavy chain gene promoter is in a state that permits liberal expression of the gene. The translocation means that the cyclin D1 gene is now governed by this highly active promoter and so cyclin D1 is produced in abundance, facilitating cell division.

Another intracellular protein that has oncogenic potential is the product of the myc gene. The myc protein binds to DNA and induces expression of a large number of genes. Aberrant activation of the myc protein is a common feature in many different types of cancer. In Burkitt lymphoma, a translocation occurs which places the coding region of the myc gene (8q24) next to the promoter region of the immunoglobulin heavy chain (14q32)

The bcl-2 translocation that is found in follicular lymphoma illustrates an anti-apoptotic mutation. The translocation shifts the coding region of the bcl-2 gene from chromosome 18q21 to the control of the heavy chain gene promoter (14q32), leading to overexpression of bcl-2. Follicular lymphoma is derived from germinal centre B cells and these cells normally do not express bcl-2.

Tumour Suppressor Genes

Tumour suppressor genes fall into two main groups. One cohort is composed of those genes which serve as inhibitory regulators of cell division and stop cells from dividing unless they receive the appopriate signal. The other group consists of genes which either correct damage to DNA before it can become established as a mutation and/or induce the cell to undergo apoptosis if the damage cannot be repaired or is too severe.

If inhibitors of cell division are themselves inhibited, the brake that they apply to mitotis is removed and the cell can divide more rapidly.

Mutation of genes which code proteins that protect the cell against the consequences of damage to its DNA potentially have more serious repercussions. Once a cell loses the ability to defend and repair its DNA, it becomes susceptible to more mutations and is therefore considerably more vulnerable to acquiring the full set of mutations that are necessary to become malignant. If defective DNA repair genes are coupled with increased mitotic activity the situation arises in which a cell that has lost the ability to repair its DNA, which will include correct replication errors that occur during mitosis, is undergoing more proliferative activity which intrinsically presents an opportunity for mutation to occur through mistakes in copying DNA.

Specific Examples

The retinoblastoma gene / protein was named due to the discovery of its role in the rare paediatric tumour, retinoblastoma. Needless to say, the retinoblastoma protein did not emerge from millions of years of evolution simply to generate a malignant tumour of the retina. Instead, the retinoblastoma protein (Rb-1) blocks mitotic activity in the cell by binding to the E2F family of transcription factors. If left to their own devices, the E2F proteins attach to DNA and allow a cell to progress through the cell cycle. The Rb-1 protein prevents this from happening and therefore stops the cell from proliferating. If cell division is required and appropriately authorised, other systems engage that raise the levels of cyclin D and cyclin E. Cyclins D and E activate cyclin dependent kinases 2, 4 and 6 and these phosophorylate Rb-1. The phosophorylated form of Rb-1 loses its grip on the E2F proteins, which are free to bind to DNA and enable proliferation of the cell.

The p53 protein has been investigated in numerous different tumours. It has a variety of functions that protect the cell against the consequences of DNA damage. Its synthesis is greatly increased if the cell suffers injury that could damage DNA. Under these circumstances p53 stops the cell from dividing, thus ensuring that if any mutations have occurred, they cannot be perpetuated in the next generation of cells. Having intervened to prevent errors from being passed on, p53 also causes the cell to synthesise the assorted proteins that can detect mutations in DNA and repair them. If all goes well with this process the levels of p53 are reduced and the cell can resume normal function. However, if the injury cannot be corrected, p53 orders the cell to begin apoptosis, thus preventing the mutations from ever having the chance to generate a tumour.

Various different enzymes exist that can detect DNA damage and repair it. They can operate because mutation often distorts the shape of the DNA molecule and this can be identified by the enzyme. Two examples are MLH-1 and MSH-2. Mutations in these genes are found in the hereditary non-polyposis coli colonic adenocarcinoma syndrome.

The adenomatous polyposis coli (APC) syndrome protein is an intracellular protein that latches onto beta-catenin and degrades it. Cytoplasmic beta-catenin can make its way to the nucleus and trigger cell division so the APC protein blocks this action.


In order for a cell to divide it has to reproduce all of its DNA. An enzyme exists which can accomplish this, DNA synthase. In order to generate a copy of the DNA, DNA synthase has to bind to one end of the chromosome and then trundle its way down the entire molecule. However, the part of DNA of the chromosome that is first latched onto by DNA synthase is covered up by the anchoring region of the enzyme and therefore cannot be read and replicated by the synthase portion. This means that the copy of the chromosome is actually a little shorter than the original.

To avoid losing valuable DNA to this phenomenon, the ends of chromosomes are formed by repeat sequences of DNA known as telomeres. These have no role in encoding proteins but are vital to allow replication to take place.

With each division of the cell the telomeres become shorter. Eventually, if nothing is done, the telomere is exhausted and further attempts at division will eat into the coding regions of the chromosome, with disastrous results. This happens after around sixty generations of cells, at which point the cells become senescent.

A solution to the problem exists in the form of telomerase. This enzyme extends the telomere back to its original length. Most cells will not be required to divide enough times to reach the telomere length threshold and do not express telomerase. However, stem cells, lymphoid cells and the germ cells in the male do require the ability to divide an indefinite number of times without burning through their entirity of their telomeres and so do express telomerase.

Telomerase is a useful enzyme for a neoplastic cell to possess and it is therefore sometimes found to be aberrantly active in tumour cells.