Arguably, the most famous gene in the human genome, the TP53 gene, can be found on chromosome 17p13.1. This gene encodes the p53 tumor suppressor protein, which happens to be the most frequently mutated protein in human cancer, with greater than half of all tumors harboring mutations at this locus (Vogelsteinet al. 2000; Petitjean et al. 2007b). In its controversial discovery, the p53 protein was first identified as an oncogene because of its association with the simian virus 40 (SV40) large T-antigen (Lane and Crawford 1979; Linzer and Levine 1979). Subsequently, it was observed that many tumors express this protein in excess quantities, suggesting once more that p53 might act as a cellular oncogene (DeLeo et al. 1979; Rotter 1983). This notion was reinforced when investigators, Eliyahu et al. and Parada et al., ectopically expressed the newly cloned p53 cDNAs into primary cells. The expression with p53 cooperated in conjunction with oncogenic Ras to transform primary cells in culture. Likewise, Wolf and colleagues overexpressed p53 in cells where endogenous p53 had been inactivated by retroviral insertions and demonstrated an increase in tumorigenicity. Thus, with a wealth of supporting evidence and papers published in top quality journals, all attesting to p53’s oncogenic characteristics, who would doubt them?
Several scientists did. Contradictions were raised when a group of investigators were having trouble replicating the newly published results describing oncogenic p53 particularly, in regards to its ability to transform primary cells. Interestingly, when several groups compared their cloned p53 cDNA sequences with each other, none where identical (Levine and Oren 2009). As a result, it has become widely acknowledged that t...
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MDM2 functions to keep p53 levels in check during unstressed cellular conditions. However, p53 is stabilized in response to a wide variety of cellular stresses including DNA damage, Radioactive Oxygen Species, hypoxia, oncogene activation, osmotic shock and even ribonucleotide depletion (Vousden and Lu 2002; Han et al. 2008). This stabilization and activation of p53 in response to stress is mediated through many post-translational modifications targeting various domains. The p53 protein is composed of an acidic N-terminal transactivation domain, a proline-rich domain, a DNA-binding domain, an oligomerization domain and a basic C-terminal regulatory domain (Laptenko and Prives 2006). The N-terminus of p53 is heavily phosphorylated in response to DNA damage, whereas the C-terminus may be phosphorylated, acetylated, neddylated, ubiquitinated or sumoylated.
Cancer occurs when cells divide uncontrollably. Cells keep dividing even though new cells are not needed. Change from normal to cancerous cells requires gene alterations.
Wang, Chih-Hung, et al. "Simian Virus 40 T Antigen Induces p53-Independent Apoptosis but does Not Suppress erbB2/neu Gene Expression in Immortalized Human Epithelial Cells." Cancer letters 137.1 (1999): 107-15.
Specifically “TP53, p16INK4A, and SMAD4. The p53 nuclear protein activates transcription of a cyclin kinase inhibitor p21WAF1/CIP1. Following genomic stress, inappropriate growth factor stimulation or expression of oncogenic ras increased expression of p53, and thus p21WAF1/CIP1 resulted in inactivation of specific CDK/cyclin complexes” (MedScape). If this transformed cell can escape internal and external fail-safe mechanisms, receive nutrients, and activate its proliferative program, it can form a mass of cancerous cells. Tumor growth can cause the loss of pancreatic functions. Another characteristic of pancreatic cancer is metastasis happens early in tumor growth, which is most likely responsible for pancreatic cancer’s aggressive
The acquisition of an immortalized proliferative potential is very important for human tumors because, otherwise, the tumors will not grow in number nor will they metastasize. Mutations in progenitor cells would not be transmitted too far as they have limited replication and proliferation ability. Thus, the growth of the tumors will be limited. Hence, if there is even a very small population of cells with the ability to proliferate continuously, there will be a source for productions of more cells for the tumor. Clonogenic assays have shown that, though most cells in a tumor have a limited ability to proliferate, a subset of cancer cells exist in these tumors that continuously proliferate and give rise to new tumors on transplantation.
The article begins by stating that the tumor suppressor p53 has great importance in the prevention of cancer growth and expansion. Although cancer is the most spoken about topic and p53’s significance against it, p53 also has a hand in ischemia, neurodegeneration, and ageing. While this tumor suppressor seems to be very busy it also regulates the repair of DNA and death of the cell, just to name a few. The activity of p53 can be seen when binding to the DNA at target sequences for transcription. It was pointed out that the doings of p53 are not designated to the nucleus such as other transcription factors as determined over time. Further mentioned in the introduction is a statement that lists this as the most studied mechanism while also related to the material covered in class is apoptosis. P53 inducts apoptosis in the by intrinsic mitochondria-mediated pathway, also transcriptionally through pro-apoptotic parts of the pathway, and in a transcription–independent way which has been recently been looked further into. As if the roles above were not plentiful enough cytoplasmic p53 is also thought to influence autophagy, movement of vesicles, signal transduction, cell metabolism and possibly stem cell expansion, but all are truly determined. Towards the end of the introductory section the authors state that there are still many mechanisms of cytoplasmic p53’s activation leading to apoptosis that are uncertain as well as some p53 missense mutants that lead to oncogenesis. The authors express that the article mainly will speak about the proper or improper activities performed by p53 on the mechanism in the cytoplasm while also looking for areas where beneficial treatments may be used.
Cancer has been an active concern in our society for the past couple decades, since we truly discovered the nature of cancer and the potency it brings along with it. However, it was not until the mid-20th century that scientists were beginning to truly understand the origin of cancer. Scientists dating back all the way to the Renaissance, when they first began performing autopsies to learn more about the human body and form, noticed abnormalities but it never clicked that it was something much worse than it seemed. Research has continued since then, and it has continued to thrive even to this day. When James Watson and Francis Crick discovered DNA and it’s chemical structure in 1962, it opened up doors that even they could not expect. With the understanding of DNA and how it affected the way we look at life, came the beginning of the understanding of mutated DNA (which is a cause of the growth of cancerous cells). In this past century, researching scientists discovered that cancer is linked with the DNA that resides in a cell’s nucleus. By ways of damage to the cells via chemicals or radiation, or even introduction of a new DNA, the cancerous cells begin to form and duplicate. We are learning more and more about cancer and how to fight it, but we still have much more to learn.
Hypermethylation of CpG islands at tumor suppressor genes turns them off, while hypomethylation leads to the instability and inappropriate activation of oncogenes and transposable elements. Methylation can be directly related to genetic mutations, an example of this case is methylated cytosine. Methylated cytosine mutates spontaneously in vivo through deamination to give thymine. According to Andy Bannister (n.d.), “37% of somatic p53 mutations and 58% of germ line mutations occur at methylated...
Thought to be an oncogene, a gene that has potential in transforming normal cells into tumor cells, p53 was regarded as the most prominent tumor suppressor gene [1]. P53 is a gene which signals apoptosis (programmed cell death) if a cell cannot be repaired due to an extensive amount of damage. As stated in the textbook, p53 regulation occurs by an E3 ubiquitin-protein ligase known as MDM2 [1]. "Controlling the controller" is a statement that describes the molecular interaction where the presence of MDM2 targets the p53 for proteosome via degradation. With three main checkpoints in cell cycle, the literature states p53 functioning from G1 into S phase in a chaotic cell [2]. The normal state of cells is to keep p53 levels low in order to prevent uncontrolled apoptosis and random cell cycle arrest from occurring. In a further note, although p53 promotes apoptosis and cell cycle arrest, cancer may result from p53 unable to recognize the problematic site. In turn, a mutation in p53 may result engaging in new activities. These activities include cellular transformation, tumor metastasis,...
My sister, Kathy, was diagnosed with cancer in 2013. I was shocked because my sister was always the healthy one among all us girls, the type of cancer, Kathy called colon cancer, Cancer that forms in the tissues of the colon. Most oncogene mutations of indisputable normal genes designate proto-oncogenes. Proto-oncogenes determine the “excellent” genes that usually rule what cell do and the way typically it distribute. Once a factor mutates (changes) into cell, it come back a "hurtful" factor that may become usefulness on or activated once it's not believe to be. Once this occurs, the cell becomes out of management, which might pass to cancer. As scientists learn additional throughout oncogenes, they will be powerful to develop a medication that inhibits or restrain them.
The cell cycle is the process by which cells progress and divide. In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates it’s DNA and divides, these are called proto-oncogenes. A proto-oncogene is a normal gene that could become an oncogene due to mutations. This process has mechanisms to ensure that errors are corrected, if they are not, the cells commit suicide (apoptosis). This process is tightly regulated by the genes within a cell’s nucleus. In cancer, as a result of genetic mutations, this process malfunctions, resulting in uncontrolled cell proliferation. Mutations in proto-oncogene or in a tumour suppressor gene allow a cancerous cell to grow and divide without the normal control imposed by the cell cycle. A change in the DNA sequence of the proto-oncogene gives rise to an oncogene, which
The American Cancer Society publishes current advances made in cancer research on their website. Many of the exciting discoveries about how best to treat the disease focus on the genetic aspects associated with certain types of cancer. In addition, treatments aimed at genetic solutions to cancer may be more effective and may cause fewer adverse side effects than traditional cancer treatments (American Can...
The mechanisms by which cancer occurs are incompletely understood. The cancer is thought to develop from cells with changed the typical mechanisms for manage of proliferation and growth. Recent proofs strengthen the notion of carcinogenesis as a genetically regulated multistage process (Mediana et al., 2008).
An ordinary human body contains approximately one trillion cells and precisely 46 chromosomes in each cell. However, the human body can be altered by a genetic mutation. Over the course of history, genetic mutations have had a large impact on the human race. They have brought harm to numerous amounts of people. Cancer, in particular, is one of the most lethal diseases. Cancer begins when a portion of DNA inside a chromosome is damaged, causing a cell to mutate. Then, the mutated cell reproduces multiple times and creates a tumor. Afterwards, cancer cells break off of the tumor, enter the bloodstream, and disperse throughout the body. If the cells break off, the tumor is considered malignant - this type of cancer is very difficult to cure. Many patients today stay optimistic for a medication to heal cancer. It is imperative to address a few of the causes and effects of cancer in order to gain a general knowledge of genetic mutations.
“Since 1990, over 6 million Americans have died of cancer, more than the combined casualties from the Civil war, WWII, and the Vietnam and Korean conflicts combined” (Faguet, p. 5). According to American Cancer Society projections, there were 1,529,560 new cases of cancer in 2010. Cancer is becoming more and more common around the world. New cancers are constantly being discovered. Researchers are finding new ways to detect cancer and treat it so that the fatality rate does not rise. However, there are some cancers that researchers have not yet discovered a cure for. It is very important for Cancer Research to continue so that one day these cancers will no longer be a treat.
Tumors are formed by the alteration of the body’s own cells. This can be caused by environmental factors such as radiation, like UV exposure, chemicals or viruses 1. These can disrupt genes that control growth and cause an increase in cell division and proliferation. Proto-oncogenes are those genes that control normal but essential cell processes that keep cell growth and death in check. Two important categories are apoptosis genes, which regulate cell death, and tumor suppressor genes, which decrease cell propagation 1 . If these genes were mutated to the point where they cannot produce a functioning protein, cell division would continue far past what it was supposed to and unhealthy cells would be allowed to live and continue to multiply. This is what creates a malignant tumor. Certain conditions in the body can also promote the growth of cancer cells. One of these is a deficiency of natural killer (NK) cells, which are able to kill cancer cells by creating a pore in the cell membrane with perforin and releasing granzymes into the cell. Low levels of perforin allow for tumor growth 1. Chronic inflammation can also ...