Compare and Contrast Tumor Suppressor Genes and Proto-Oncogenes free essay sample

Compare and contrast tumour suppressor genes and proto-oncogenes. Discuss an example of how recent advances in our understanding of these genes have led to the development of a novel therapy that is being used in the treatment of human cancer. Cancer known in medicine as a malignant neoplasm is one of the biggest killers worldwide. In 2007, cancer caused roughly 13% (7. 9 million) of the planet’s deaths (Jemal, 2011). This will more greatly affect an aging society such as ours in years to come, and yet it is already the foremost cause of death in the developed world. The main reason cancer causes so many fatalities the body’s inability to mount an effective response to the failure of DNA replication within the body. This results in a mass of uncontrolled tissue proliferation which eventually leads to death. Approximately, 50% of all people who get cancer will eventually succumb to the disease (Jemal, 2011). It is therefore essential that new methods for controlling the disease are found to improve the prognosis of suffers. Tumour suppressor genes normally function to uncontrolled proliferation of cells within the body. They do this through a variety of means, they might prevent inappropriate progression of the cell cycle, or drive already cancerous cells towards apoptosis, and others simply check for errors during replication increasing fidelity (Sherr, 2004). Mutant versions that are present in cancers have lost the function to perform any of these properly. In contrast to oncogenes, tumour suppressor cells generally follow the two hit hypothesis (Knudson, 2001). The hypothesis indicates that two mutations must affect both of the normally dominant tumour suppressor cells before a mutant phenotype is seen. Proto-Oncogenes are usually recessive, hence it only takes a single mutation to one of the alleles (to become dominant as it is a gain of function mutation) before a mutant phenotype is seen. Although, this is not true for all cancers, and sometimes the tumour suppressing genes can exhibit haploinsuffciency which allows cancer to develop with only one mutation to one of the alleles (Knudson, 1971). Mutations (for most cancers) must appear in both tumour suppressing genes and oncogenes for cancers to form. The tumour suppressing genes and oncogenes act in complementary fashion to one another; one pulls forward, and the other pushes back ensuring that the cell cycle occurs in a controlled manner (Sherr, 2004). Oncogenes were discovered in the 1960s, when it was discovered that some animal cancers such as lymphomas were caused by viruses. Some of these viruses were notable due to the simplicity of their RNA genome. These viruses only had three distinct transcription units, involved in the replication of the virus (coat proteins and reverse transcriptase etc. ), and an extra gene. This was an oncogene. When oncogenes are properly functioning they are termed proto-oncogenes (Todd R, 1999). Their normal function is to control cell proliferation. These function in growth signalling pathways, and conversely to tumour suppressing cells are activated through a gain in function rather than a loss of it. This occurs in two ways, by producing more of a product, or producing a subtly different product, as a result of a mutation similar to tumour suppressor genes (Croce, 2008). Oncogenes play a particularly strong role in the development of breast cancers. Often the normal ERBB2 and other related genes are amplified in late stage neuroblastomas and rhabdomyosarcomas. ERBB2 encodes HER2 which is a member of the epidermal growth factor receptor, and a factor in 30% of all breast cancers. Both tumour suppressor and oncogene gene mutations can be acquired through exposure to carcinogens or inherited in the form of genetic defects: for example, a defective APC gene causes familial adenomatous polyposis which has been shown to run through families (Amos-Landgraf, 2007). The increased understanding of tumour suppressor genes and oncogenes has helped scientists develop novel techniques when dealing with cancer. One of the most exciting is the direct targeting of some of the genes which cause cancer. In particular regard to oncogenes as it is significantly easier to repress expression in cancerous comparison to restoring normal gene functions which would require inserting exogenous DNA into cancer cells. The insertion of the DNA provides an almost insurmountable problem, which has not yet been circumvented fully. Furthermore, cancerous cells may have several mutations which need to be undone, and any treatment will unfortunately probably be undirected and thus not suitable for chemotherapy. Although some successful experiments have been done (Ramesh and Al-et, 2001). The aforementioned HER2 is the target of the monoclonal antibody trastuzumab. Trastuzumab was the first drug which was specifically designed to repress the activity of a oncogene and is one of the most well known. The mechanism which trastuzumab uses to stop cancer cell proliferation is unknown. It is hypothesised that it binds to the domain IV of the extracellular segment of HER2, and as a result causes cell cycle arrest by inducing immune cells to target the cell thus reducing cell proliferation, and the prognosis of any suffers (Hyun-Soo Cho, 2003). Another postulated mode of action is that it downregulates HER2/neu. This is done by disrupting dimerisation of the HER2 cell hence not allowing it to promote cell growth, as it would in a healthy person. It does this by regulating cdc2 (a protein that keeps mitosis under control), by ensuring the regulatory protein p27Kip1 is allowed to inhibit cdc2. In tumour cells p27Kip1 doesn’t move into the nucleus and is inhibited by HER2 (Molina and Et-al, 2001). The manufacturers of trastuzumab cite that the drug has had a â€Å"major impact in the treatment of HER-2 positive metastatic breast cancer† (Tan, 2003), however following studies have been less positive about the benefits of drug. In one trail only one patient in 13 saw any benefit in result of being administered the drug. Trastuzumab is also very expensive, as much as $70,000 for a full course (Fleck, 2006). Trastuzumab is only the first of many therapies that will involve oncogenes and tumour suppressor genes, and the area remains a very intensive area of research. Indeed, there are many new drugs coming to market and through clinical trials which will hopefully be even more effective than Trastuzumab is. They will be used to treat a much wider range of cancers, and as a result increase the standard of living across the globe. Words: 996 Bibliography AMOS-LANDGRAF, J. 007. A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 104, 4036 41 CROCE, C. M. 2008. Oncogenes and Cancer. The New England Journal of Medicine, 358, 502 11. FLECK, L. 2006. The costs of caring: Who pays? Who profits? Who panders? . Hastings Central Report, 36, 13 17. HYUN-SOO CHO, E. A. 2003. Structure of th e extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature Reviews Cancer, 421, 756 760. JEMAL, A. 2011. Global Cancer Statistics. CA: A Cancer Journal for Clinicians, 61, 69 90. KNUDSON, A. G. 1971. Mutation and Cancer: Statistical Study of Retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America, 68, 820 823. KNUDSON, A. G. 2001. Two Genetic Hits (More or Less) to Cancer. Nature Reviews Cancer, 1, 157 162. MOLINA, M. A. amp; ET-AL 2001. Trastuzumab (Herceptin), a Humanized Anti-HER2 Receptor Monoclonal Antibody, Inhibits Basal and Activated HER2 Ectodomain Cleavage in Breast Cancer Cells. Cancer Research, 61, 4744. RAMESH, R. amp; AL-ET 2001. Successful Treatment of Primary and Disseminated Human Lung Cancers by Systemic Delivery of Tumor Suppressor Genes Using an Improved Liposome Vector. Molecular Therapy 3, 337 350 SHERR, C. 2004. Principles of tumor suppression. Cell, 116, 235 46. TAN, A. R. 2003. Ongoing adjuvant trials with trastuzumab in breast cancer. Seminars in Oncology 30, 54 64. TODD R, W. D. 1999. Oncogenes. Anticancer Research, 19, 4729.