Oncogene
Introduction
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated or expressed at high levels. Most normal cells will undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered and malfunctioning. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead.
Discovery
The concept of oncogenes was first proposed in the early 20th century by the German biologist Theodor Boveri. He hypothesized that certain genes, when dysregulated, could contribute to the malignant transformation of cells. However, it was not until the 1970s that the first oncogenes were actually identified, thanks to the pioneering work of scientists such as Harold Varmus and J. Michael Bishop.
Classification
Oncogenes can be classified into several categories based on their function and the signaling pathways they affect. These include growth factors, growth factor receptors, signal transducers, transcription factors, and apoptosis regulators.
Growth Factors
Growth factors are proteins that stimulate cell proliferation. Oncogenic growth factors can lead to excessive cell division and the formation of tumors. Examples include the Epidermal Growth Factor (EGF) and the Platelet-derived Growth Factor (PDGF).
Growth Factor Receptors
Growth factor receptors are proteins located on the cell surface that bind to growth factors and initiate a signal transduction cascade leading to cell proliferation. Oncogenic growth factor receptors can be constitutively active, leading to uncontrolled cell division. Examples include the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal growth factor Receptor 2 (HER2).
Signal Transducers
Signal transducers are proteins that transmit signals from the cell surface to the nucleus, leading to changes in gene expression. Oncogenic signal transducers can lead to the inappropriate activation of signaling pathways that promote cell proliferation. Examples include the Ras protein and the Src family kinases.
Transcription Factors
Transcription factors are proteins that bind to specific DNA sequences and control the transcription of genetic information from DNA to RNA. Oncogenic transcription factors can lead to the inappropriate expression of genes that promote cell proliferation. Examples include the Myc and the Jun protein.
Apoptosis Regulators
Apoptosis regulators are proteins that control the process of programmed cell death. Oncogenic apoptosis regulators can prevent the death of cells that should be eliminated, leading to the accumulation of abnormal cells and the formation of tumors. Examples include the Bcl-2 and the Survivin.
Mechanisms of Oncogene Activation
Oncogenes can be activated through a variety of mechanisms, including point mutations, gene amplification, chromosomal translocation, and viral insertion.
Point Mutations
Point mutations are changes in a single nucleotide base pair in a DNA sequence. These mutations can result in the production of a protein with altered function. For example, a point mutation in the Ras gene can lead to the production of a Ras protein that is constitutively active, promoting uncontrolled cell division.
Gene Amplification
Gene amplification is the production of multiple copies of a gene. This can result in the overexpression of the gene product, leading to uncontrolled cell proliferation. For example, amplification of the HER2 gene can result in the overexpression of the HER2 receptor, promoting the growth of breast cancer cells.
Chromosomal Translocation
Chromosomal translocation is the rearrangement of parts between nonhomologous chromosomes. This can result in the production of a fusion protein with oncogenic properties. For example, the Philadelphia chromosome is a translocation between chromosomes 9 and 22 that results in the production of the BCR-ABL fusion protein, which is associated with chronic myeloid leukemia.
Viral Insertion
Viral insertion is the integration of viral DNA into the host genome. This can result in the activation of oncogenes or the inactivation of tumor suppressor genes, leading to the development of cancer. For example, the human papillomavirus (HPV) can integrate into the host genome and disrupt the function of the p53 tumor suppressor gene, promoting the development of cervical cancer.
Oncogenes and Cancer Treatment
The identification of oncogenes has had a profound impact on the treatment of cancer. Many targeted therapies have been developed to inhibit the function of specific oncogenes. These include monoclonal antibodies, small molecule inhibitors, and gene therapy.
Monoclonal Antibodies
Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. They can be designed to specifically target oncogenic proteins. For example, the drug trastuzumab is a monoclonal antibody that targets the HER2 receptor, and is used in the treatment of HER2-positive breast cancer.
Small Molecule Inhibitors
Small molecule inhibitors are low molecular weight organic compounds that can inhibit the function of oncogenic proteins. For example, the drug imatinib is a small molecule inhibitor that targets the BCR-ABL fusion protein, and is used in the treatment of chronic myeloid leukemia.
Gene Therapy
Gene therapy involves the introduction, removal, or change in genetic material within a patient's cells to treat or prevent disease. This approach can be used to target oncogenes. For example, antisense oligonucleotides can be used to inhibit the expression of oncogenes at the RNA level.
See Also
References
1. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57-70. 2. Vogelstein, B., & Kinzler, K. W. (2004). Cancer genes and the pathways they control. Nature medicine, 10(8), 789-799. 3. Stratton, M. R., Campbell, P. J., & Futreal, P. A. (2009). The cancer genome. Nature, 458(7239), 719-724.