P53: A Tumor Suppressor Gene

In vitro: In lymphocytes, Cladribine caused accumulation of DNA strand breaks, subsequently activating the tumor suppressor p53. In MM1.S, RPMI8226 and U266 cells, Cladribine dose-dependently inhibited cell proliferation and survival [1].

The TP53 gene encodes a 53 kDa protein [18] that is involved in mediating cellular responses to various forms of stress signals [22]. Following these signals, the biological responses mediated by P53 can be attributed to its ability to act as a tetrameric transcription factor promoting the expression of genes involved in cell cycle arrest, apoptosis, DNA repair,

By helping to repair DNA, the BRCA2 protein plays a critical role in maintaining the stability of a cell 's genetic information. The cancer risk caused by BRCA2 mutations is inherited in a dominant fashion, even though usually only one mutated allele is directly inherited. This is because people with the mutation are likely to acquire a second mutation, leading to the dominant expression of the cancer. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations. Because humans have a diploid genome, each cell has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling, inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed, however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss of the functional copy is called loss of heterozygosity (LOH). Any resulting errors in DNA repair may result in cell death or a cancerous transformation of the cell.

Proto-oncogenes are genes that code for cell division enhancing proteins or proteins that prevent typical death in a cell. When these genes become mutated, they are called oncogenes. The cell division stimulating proteins that proto-oncogenes create work in a signal transduction cascade. The signal transduction cascade is the set of steps through which a receptor in the membrane receives the signal, which is a growth factor in this case, and activates different proteins and factors, leading to the transcription factor (a protein that binds to DNA to affect the transcription of a gene) being activated and entering the nucleus. In the case of proto-oncogenes, the signal transduction cascade leads to cell division. Proto-oncogenes can become oncogenes when a proto-oncogene is mutated, the genes are rearranged, or the number of proto-oncogene copies increases. The

TP53, also called tumor protein 53 is a tumor suppressor gene that encodes p53 and acts as a control center for the cell to act on when stressed (Brachova). Human p53 is a nuclear phsophoprotein of molecular weight 53kDa located on chromosome 17 containing 11 exons and 10 introns (Ling). One of its primary roles is as a transcription factor and in its active state is a homotetramer comprised of four 393 amino acid residues (Joerger , The tumor suppressor p53). Another main role p53 plays is as a tumor suppressor and once activated, protects against cancer by “functioning as a sequence-specific transcription factor, through protein-protein interactions, activating cell cycle arrest, apoptosis, and DNA damage repair (Brachova).”

The ability of p53 to regulate metabolism is also associated with the ability to regulate cellular ROS levels. As previously mentioned, p53 can either remove damaged cells that have suffered sustained oxidative stress, or limit levels of ROS in order to lower oxidative stress and consequently, potential cell damage. Through the regulation of carbohydrate and lipid metabolism, p53 is able to influence the response to ROS accordingly. By driving the expression of TIGAR and promoting PPP activity, p53 can increase the production of NAPDH, which can be used to generate the cellular antioxidant GSH (Bensaad 2006). Moreover, at the expense of nucleotide synthesis, p53 can also promote GSH synthesis following serine starvation, thereby lowering ROS

An irritant, such as cigarette smoke, effects the cells of the epithelium lining. Initially the body can repair the cell, but with repeated exposure the cells of the lungs become damaged and grow uncontrollably. P53 is a gene for various downstream targets that are involved in cell progression, DNA repair and regulation of cells that undergo apoptosis. Mutations to P53 hinder its normal tumor suppressing capabilities. Therefore, DNA damage remains unchecked, faulty cells proceed through the cell cycle and apoptosis is invaded. All these factors create a genetic condition where the cell is more susceptible to further mutation. If the cancer grows large enough, it can affect the organ by closing off the aveoli, leading to shortness of

1. Proto-oncogenes and tumor suppression genes are both used to help regulate the cell cycle. Tumor suppression genes produce proteins that inhibit cell division, and proto-oncogenes produce proteins that stimulate cell growth and division. The balance between the activities of these two genes ensure cells are dividing at a suitable rate for their body. Mutations affect these cells in two different ways. When mutation occurs, proto-oncogenes become oncogenes. Oncogenes promote excessive growth and causes the cells to divide excessively, even when it is unnecessary for the cell to keep dividing. When mutation occurs for tumor suppression genes, the tumor suppression genes can become inactive. Because tumor suppression genes inhibit and lessen

Cancer is a difficult disease to combat in any organism. Whether cancer comes through a carcinogen, virus, bacteria, or genetic history the process is the same for most cancers. DNA is damaged in a cell and stops the process of apoptosis and the cell divides uncontrollably. Eventually the cells become a tumor and reach the bloodstream spreading through metastasis. In response to this many organisms have a defense to help control and destroy these cells through a protein called p53. This protein is coded for by the gene Tumor Protein 53 or TP53 and helps to control the cells ability to divide rapidly. This gene can be found in small organisms like mice to large mammals like elephants and whales. Cancer’s success is dependent on a mutation in

The pathophysiological mechanisms are currently unknown, however it is believed that mutations in ribosomal proteins disrupt ribosome biogenesis, leading to red cell aplasia.1,2 Defective ribosome biogenesis is believed to lead to p53 activation which may cause apoptosis and cell cycle

These genes cause the cell-division process to decelerate, DNA mistakes are corrected, and apoptosis occurs so mutations are limited and preventing cancer cells from forming. When the tumor suppressor genes do not function accordingly, this creates issues with cell division and mutations and then cancer can form. Tumor suppressor genes cause cancer when they are inactive, compared to the oncogene when they cause cancer because they are activated. An example of a tumor suppressor gene would be retinoblastoma, an eye cancer, mostly associated with children, that affects the retina. This disease can be inherited and inherited distortions of tumor suppressor genes have been discovered in families. These genes can sometimes cause cancer to be inherited, but not always because normally the mutations are acquired. A specific trans-activator is a part of gene regulation that raises the rate of a specific gene that can later be activated by a response, or are unnaturally expressed. These genes are needed for domains of the p53 protein, and also are needed for protein expression and protein regulation.

Cancer is the uncontrolled division and growth of cells within the body. (Appendix 1) These cells are usually abnormal and are caused by mutations in genes that control the cell growth and replication. These cells damage the normal function of organs and can form tumours. Anti-cancer drugs work using number of strategies that interferes with the mitosis of the body cells, which in turn slows down the growth of the cancerous tissues. Anticancer drugs have distinct mechanisms of action which may vary in their effects on different types of cancer cells. These mechanisms of action are divided into three main categories. Anticancer drugs generally do one of the following, stop the synthesis of the pre-cursors of the DNA synthesis, damage the nucleic acid of the cell or affect the formation of the mitotic spindle. This is displayed in appendix 2. All three interfere with the division of the cells, which in turn slows down the growth of the cancerous tissue.

These can cause mutations which can lead to a change of function and creates tumors. These tumors can affect the digestion and respiration, leading to death. A type of gene that regulates how fast cells divide is BRCA1 which belongs to tumor suppressor genes. The cells go through a process for cell division called the cell cycle. This cell cycle contains many checkpoints in which the proteins regulate how fast the cell can continue. BRCA1 helps some forms of mutations in the DNA. If the cell is damaged, BRCA1 keeps it from dividing until repaired. In your body, you have two copies of BRCA1 but you only need one fully functioning gene. When the BRCA1 is ineffective the cell is allowed to divide and accumulates mutations. These mutations may cause the cell to become less specialized and it can stop its function in the tissue. If all this occurs, then most likely they will develop into cancer

Cancer, also known as a malignant tumor, is a disease in which some cells in the body multiply uncontrollably leading to a mass of abnormal cells (“What is Cancer”).This is the result of damage to the DNA (deoxyribonucleic acid) of a normal healthy cell which causes the natural biological function of the cell behavior to become altered (Mandal). Normal cell behavior is directed by the DNA which regulates the growth and death of the cell among other things (Mandal). When a normal cell’s DNA is damaged, the cell tries to repair the DNA and if it is unable to

It may be possible to correct an abnormality in a tumor suppressor gene such as P53 by inserting a copy of the wild-type gene; in fact, insertion of the wild-type P53 gene into P53-deficient tumor cells has been shown to result in the death of tumor cells (3). This has significant implications, since P53 alterations are the most common genetic abnormalities in human cancers. The over expression of an oncogene such as K-RAS can be blocked at the genetic level by integration of an antisense gene whose transcript binds specifically to the oncogene RNA, disabling its capacity to produce protein. Experiments in vitro and in vivo have demonstrated that when an antisense K-RAS vector is integrated into lung cancer cells that over express K-RAS their tumorigenicity is decreased (4).