Mutations Tumour Genes
The Effects of Loss or Mutations of Tumour Suppressor Genes
Cells of multicellular organisms have a variety of mechanisms in place to control their proliferation. However, one of the most common causes of human death in the Western world is cancer, a disease caused when cells become selfish proliferating cells at the cost of the organism as a whole. From the pattern of cancer incidence with age it was long hypothesised that tumours arise due to genetic changes in cells that allow them to overcome normal controls over proliferation. It is now known that multiple genetic changes occur within cells enabling tumour formation. When cells from patients' tumours are investigated intermediate steps in the development process from normal cells to invasive cancers can be identified. Tumour cells therefore evolve via a succession of genetic changes that confer growth advantages. Many genes involved in this transformation have now been identified. Such genes can be grouped into two major classes oncogenes and tumour suppressor genes.
Oncogenes and Tumour suppressor genes
Oncogenes are genes, which promote the formation of tumours. They were first identified in oncoviruses, which are viruses that cause cancer by introducing oncogenes to host cells. Subsequently endogenous homologues were identified within mammalian cells, which act as oncogenes when misregulated.
Tumour suppressor genes are involved in cellular pathways, which normally help to prevent tumour formation (Sherr, 2004). Thus when the gene is mutated and can no longer function properly in that protective pathway the cell is no longer suppressed from tumour formation. Tumour suppressor genes were first identified in families where the incidence of certain types of cancer is unusually high. Their predisposition to cancer is due to the inheritance of lost or mutated genes, which were then named tumour suppressor genes (Lohmann and Gallie, 2004). In such families cancer onset tends to occur early in life. In cancers occurring later in life mutations in the same genes have been identified. Therefore these genes, as well as causing a cancer risk if inherited in a mutated form, confer cancer risk if they become mutated during a person's lifetime.
For a number of tumour suppressor genes the molecular basis of their activity is now understood, for example the tumour suppressor gene phosphatase and tensin homolog (PTEN). In the main body of this essay I discuss the molecular mechanisms involved that lead to a predisposition of cancer following loss of or mutational change to PTEN.
Discovery of PTEN as a tumour suppressor gene
Like many tumour suppressor genes PTEN was initially discovered due to its ability to confer a predisposition to cancer if inherited in a mutated form. Cowden syndrome is an inherited disorder, which is usually initially diagnosed due to the presence of hamartomas, which are small, noncancerous growths most commonly found on the skin and mucous membranes. Sufferers of Cowden syndrome carry an increased risk of developing certain forms of cancer, including breast, thyroid, and uterus cancer. Women with Cowden syndrome have a 25-50% lifetime risk of developing breast cancer (Gustafson et al., 2007), much higher than the general risk of less than 1% (Lester, 2007). More than 70 different mutations in the PTEN gene have been identified in people with Cowden syndrome. These mutations can be a small number of base pair changes in the DNA or large deletions. Mutations occur that either alter activity due to mutations in the protein-coding region itself or affect expression due to mutation in the promoter region (Teresi et al., 2007). PTEN gene mutations cause several other hereditary disorders characterized by the development of hamartomas. These disorders include Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. In general disorders caused by PTEN mutations are called PTEN hamartoma tumor syndromes (PHTS) (Lopiccolo et al., 2007). Since its discovery as the cause of PHTS, mutations in PTEN have been found in many human cancers in patients who do not have a hereditary PTEN mutation. PTEN is frequently inactivated in glioblastoma, endometrial cancer, prostate cancer, and reduced expression is found in many other tumours including lung and breast cancers (Noro et al., 2007, Tate et al., 2007, Hu et al., 2007, Frattini et al., 2007, Chang et al., 2007).
Physiological role of the PTEN protein
Before the role of PTEN mutation involved in tumour development can be understood at the molecular level, its role in normal cell function needs to be understood:
PTEN encodes an enzyme, which is present in nearly all tissues of the body. It is a phosphodiesterase. Its substrate is phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), from which it removes the 3' phosphate group. PtdIns(3,4,5)P3 is an important component of cell signalling cascades, which promote the survival of cells. PtdIns(3,4,5)P3 is a lipid component of the cell membrane, which is produced by PI3-kinases. PI-3 kinases are activated by cell surface receptors such as G-protein coupled receptors or receptor tyrosine kinases. Survival signals are therefore transmitted from cell surface receptor to PI3-kinases, which lead to an increase in the levels of PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 initiates signalling cascades, as downstream proteins of the cascade are recruited to the cell membrane due to pleckstrin homology (PH) domains, which bind with high affinity to PtdIns(3,4,5)P3. One such downstream signalling protein with a PH domain is the Akt, which is a known oncogene. Akt promotes cell survival by inhibiting apoptosis. For example Akt phosphorylates BAD, which is a pro-apoptotic protein. This makes BAD dissociate from a pro-apoptotic complex negating its apoptotic promotion. Akt also activates the transcription factor NF-κB via activation of IκB kinase (IKK), which acts to phosphorylate the inhibitor of NF-κB (IκB) causing its dissocation from NF-κB and thus allowing NF-κB to promote transcription of pro-survival genes (Song et al., 2005). PTEN acts to counteract such pro-survival signalling pathways by reducing the levels of PtdIns(3,4,5)P3.
The effect of PTEN loss of function
When the signalling pathway outlined above is out of balance, either due to lack of PTEN function or to an excess of Akt function then the cell is more likely to survive. The normal controls on cell division are therefore disrupted and cells are more likely to develop into tumours. The key role of PTEN in maintaining this balance is illustrated by the fact that PTEN is one of the most commonly lost tumour suppressors in human cancer (Li and Ross, 2007).
References
Chang, D., Wang, T. Y., Li, H. C., Wei, J. C. and Song, J. X. (2007) Dis Esophagus, 20, 491-6.
Frattini, M., Saletti, P., Romagnani, E., Martin, V., Molinari, F., Ghisletta, M., Camponovo, A., Etienne, L. L., Cavalli, F. and Mazzucchelli, L. (2007) Br J Cancer, 97, 1139-45.
Gustafson, S., Zbuk, K. M., Scacheri, C. and Eng, C. (2007) Semin Oncol, 34, 428-34.
Hu, T. H., Wang, C. C., Huang, C. C., Chen, C. L., Hung, C. H., Chen, C. H., Wang, J. H., Lu, S. N., Lee, C. M., Changchien, C. S. and Tai, M. H. (2007) Oncol Rep, 18, 1417-26.
Lester, J. (2007) Clin J Oncol Nurs, 11, 619-22.
Li, L. and Ross, A. H. (2007) J Cell Biochem, 102, 1368-74.
Lohmann, D. R. and Gallie, B. L. (2004) Am J Med Genet C Semin Med Genet, 129, 23-8.
Lopiccolo, J., Ballas, M. S. and Dennis, P. A. (2007) Crit Rev Oncol Hematol, 63, 203-14.
Noro, R., Gemma, A., Miyanaga, A., Kosaihira, S., Minegishi, Y., Nara, M., Kokubo, Y., Seike, M., Kataoka, K., Matsuda, K., Okano, T., Yoshimura, A. and Kudoh, S. (2007) Int J Oncol, 31, 1157-63.
Sherr, C. J. (2004) Cell, 116, 235-46.
Song, G., Ouyang, G. and Bao, S. (2005) J Cell Mol Med, 9, 59-71.
Tate, G., Suzuki, T. and Mitsuya, T. (2007) Cancer Genet Cytogenet, 178, 160-2.
Teresi, R. E., Zbuk, K. M., Pezzolesi, M. G., Waite, K. A. and Eng, C. (2007) Am J Hum Genet, 81, 756-67.
We provide a professional essay writing service that thousands of our customers use as an effective way of improving their grades, improving their research and saving them lots of time.
