P53 has been known to be effective in the suppression of tumors for some time, but as more tests are done a greater understanding of its roles within the body become more apparent. The mechanisms which this gene is known to function in are becoming increasingly abundant as its influence can be seen in individuals with an array of problems. The transcription of this gene is key in many areas, and the control of that transcription is important to determining which role this gene will play once activated. This article looked at the exploitation of this gene in new drug studies that elided positive results on the therapeutic properties of this gene beyond tumor suppression. Despite this there is still much researchers must discover before we will fully understand this gene and all of it functions. P53 is known as a transcription factor and has been observed in the regulation of several downstream genes. These encode for both proteins as well as microarrays that go on to determine the response of P53. One function of this gene that is looked at more closely is its ability to inhibit cell proliferation. It can do this by first blocking the progression of the cell cycle, or by the promotion of apoptotic events. P53 has traditionally been studied for its role in cancer, especially tumor suppression, but as our knowledge on this gene grows so does the range of its applications.
Currently, small molecule drugs are being studied for their abilities to activate and stabilize this protein. These drugs often focused on altering the ability of Mdm2, this is done to target P53 and degrade it. Drug screens that are cell-based are being used in studies to identify sirtuins-protein deacetylases inhibitors that can restrict the activity of P53. Other studies being conducted on patients in these trials that show tumors that retain the wild type P53. These studies led to a larger debate about the effects of systemic activation of this gene in normal tissues and its potential for toxicity. When Mdm2is observed to be absent from animal tissues in trial the expression of P53 becomes detrimental. But trials with Mdm2-inhibiting drugs has been seen to be less effective but has shown to be easier for the individual to tolerate. This is thought to be since these drugs are not genotoxic, so are thought to be able to reduce the damage that can occur during traditional chemotherapies, because of this they are thought to function better in cells that are undergoing a great amount of damage, such as patients in chemotherapy or who are receiving radiation.
The restoration of P53 function in cells where it has been mutated has been observed to be more complicated that the medications trials previously mentioned. Some studies were successful in showing the refolding of the mutants to restore some of the wild type properties. The mutations were associated in human studies with a worse prognosis, likely due to the added difficulty of the process of restoration as opposed to activation. Retention of the wild type was seen to be important in studies on breast cancer and showed a poor response to treatment. The effect of this wild type was thought to be useful for therapeutic approaches in the tumor cells, a failure to create a P53, edited response would make the individual more sensitive to cytotoxic drugs. This idea was then expanded on to look at the ability of P53 to protect normal cells during the treatment of mutant P53 alleles. A similar concept was applied to the chemoprotection of normal tissues. A good deal of the toxicity from genotoxic chemotherapies is due to the activation, and P53-induced death of radiosensitive cells.
Specifically looking at the hematopoietic system that includes the gut lining and various tissue types. Inhibition of this gene in normal cells was observed to increase an individual’s tolerance to harsh therapies and radiation. This is important because it suggests that the side effects of genotoxins ma be avoided by the short-term inhibition of P53. While it is less studied, researchers have recently found that P53-inhibitory compounds could be beneficial in curing ischemia and Parkinson’s. The section of this article that discussed P53 and its involvement in tumor suppression began by discussing the two ways P53 can suppress tumors, by promoting apoptotic events, and by blocking cell cycle progression. The activation of this gene is caused by many different stress signals that are responses to several different forms of damage. A few examples of these the article gave were, genotoxic damage, oncogene activation, the loss of normal cell contacts, and hypoxia. Then it goes on to explain how much more complex the research of these gene has become since those initial findings were observed.
The researchers found that the activation of P53 can be modified to more effectively promote cell death. They also investigated the molecular mechanisms that were observed to have an association with the control of the P53 responses. Many models show that P53 can function to induce apoptosis, and this is often seen as the main way P53 destroys cancer cells. But as research continues the studies are beginning to show that the other functions of P53 are equally as important in the fight against tumorous cells.
The identification of PUMA was evidence of this. PUMA is described as a “P53-upregulated modulator of apoptosis.” This is seen inn studies as a moderator for the apoptotic activity, it is also a Bcl-2 homology domain 3-only protein. This can induce programed cell death from the mitochondrial pathway, studies showed this was important in the response to the activation of P53. The loss of PUMA can increase the tumorigenesis that is often led by the Myc oncogene. This suggests that the P53 gene can retain its ability to suppress tumors without a direct apoptotic response.
Then the article goes on to bring up the antiangiogenic properties of P53 but move on to focus on its ability to inhibit growth and proliferation in cells. It does this by stopping the cell cycles progression, through the transcription of the CDK inhibitor P21. But many other target genes also activate this transcription. P21’s induction is sensitive even to low levels of P53 proteins. This suggests that the temporary block in the G1 phase of the cell cycle allows the cell to survive until the problem is solved. Another key role discussed was P53’s role in senescence. Senescence has been linked to the inhibition of tumor progression, and P53 has been identified as a key player in this process. Its effects seem to be the result of a change in the number of certain proteins. Then the article goes on to talk about the role of P53 in preventing future replication of cancer cells, but it can also contribute to cell survival.
Another group of genes that can be induced by P53 that, as the article explains, “act similarly to antioxidants by decreasing the levels of intracellular reactive oxygen species” that can also lead to a decreased susceptibility to apoptosis. The article suggests that P53 could have this function because the destruction of cells causes stress, and because that is not an ideal response, although the most efficient, these functions are designed to reduce that stress. This suggests that senescence also plays a role in overall survival despite tumorous cells. Oncogenic changes that function to encourage cell proliferation in cancer cells and survival are often observed with changes in cell metabolism that have shown to be correlated with the support of tumor development. This change in the metabolic pathway can be beneficial to many things, a few that the article listed included, “the ability to survive under adverse conitions, the ability to mobilize anabolic pathways that generate macromolecules necessary for growth, and the ability to limit oxidative damage.”
P53 can become activated form metabolic changes, and the response is mediated by AMP-activated protein kinase, AMPK. AMPK is an important part of the response to bioenergetic stress. The response led by P53 is helpful in insuring the coordination of cell growth and proliferation. P53 is also involved in response to starvation, which can lead to autophagy. This article looked at the gene P53, and its role in tumor suppression and other therapeutic properties. This is a very broad topic, so the review looked more specifically at the mechanisms that are known to signal P53, its regulation within the body, and its relation to closer members in its gene family such as P63 and P73. It also looked at the regulation, turnover, and localization of this gene, its isoforms, and the consequences that can occur with this gene during cancer development.
This article begins with P53’s role in tumor suppression, looking at Then the article goes on to discuss what happens when this gene is altered and malfunctions to promote tumor growth. It then comes to an end by discussing other pathologies that this gene has shown to be involved in the processes of. Then discusses the effect of stress on P53, its locality and the modification of the regulators effect on this gene, as well as the other therapeutic uses for this gene focusing on modern drugs that are in testing. The focus of this article is on how the activation and responses of P53 are mediated within the cell. It looks at various research projects that all show links from other genes and proteins to P53 and its ability to suppress tumors. It also discusses the newer studies being done that show that this gene has therapeutic properties beyond tumor suppression.
I liked this article it seemed more approachable to an average audience, the implications of the research were well explained. The research itself was also explained in a very approachable way. I did find that while this made the article more accessible than the previous article it did also show less of the actual research that was done. This article was more of a general explanation of research being done in the field rather than the results of the experiments done.
I think as we expand our research in the field of systems biology research of gene like P53 will become easier. The more we research the connectivity of genes and their responses the more likely we are to understand their true function. I think looking for all the applications of a gene rather than focusing in depth on a known function is a good way to approach understanding cells. Such broad approach seems likely to achieve more effective results when looking for cures in my opinion it allows researchers to gain a fuller understanding of the problem they are attacking and all the ways they could attempt to attack it.
