Prevalence Of P53 Alterations In Human Cancer Biology Essay

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The last few decades or so there has been a rapid growth in our understanding of the molecular basis of cancer. Cancer can arise from any part of the human body. It represents a whole spectrum of human diseases. Caners are caused by the dysfunction of the human genes or its related processes. It is a complex process but underlying these are altered genes.

The cancer and its relationship to genes stand as one of the major area of study through which we can unlock the mysteries of cancer. There are several studies underway on different aspects of cancer and its biomedical properties. These studies have provided enormous knowledge in understanding of the cellular processes. There are several notable similarities between infectious diseases and cancers, both were common and fearsome ailments, was shrouded in mystery and superstition. The revolutionary research in infectious disease foreshadowed a similar breakthrough in cancer research. James Watson, Francis Crick and their collaborators discovered the DNA. Subsequent to it the cracking of the genetic code opened the door to the explosion in molecular biological research. A cancer gene can be defined as a variant of a gene that increases cancer risk, or promotes the development of cancer. The discovery of oncogenes, together with improvements in cytogenetics, resulted in an amalgamation of these two fields of research and led to the dawning of an understanding of how cancers might result from the breakdown of normal cellular homeostatic mechanisms.

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Cells also contain special genes called proto-oncogenes. These proto-oncogenes are responsible for programmed growth in development or repair. They play a major role in co-ordinating our growth from a single fertilized egg cell into an adult. When development or tissue repair is complete, the cell growth is switched off. This switch off mechanism is a function of Tumour suppressor genes. Cancer-causing agents or spontaneous genetic mutation change the proto-oncogenes into potentially cancer-causing oncogenes, as they promote growth where and when they should not. Similarly genes that inhibit abnormal proliferation, if it loses its function can cause abnormal proliferation. Spontaneous genetic mutation increases as we get older as our DNA repair processes become less efficient. When an oncogene is active in a cell, the cell doesn't require growth signals to grow so that the "switched-on" mechanism of growth and repair continues instead of being "switched off " as it should be, and the cells that are produced do not later undergo apoptosis (self destruction) when they are not wanted

P53 gene was first identified in 1979 by the efforts of Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old. [2] , [3] The human TP53 gene was cloned in 1984 [4] and further investigation revealed the full length clone in 1985. [5] It was shown at that time that this new found gene was responsible for many cellular responses to DNA damage, it varies from a transient growth arrest to allow the cell to repair the DNA damage, or it can be an instruction to the cell to undergo apoptosis if the damage was too great. p53 protein is a transcription factor that switches on expression of genes that regulate the cell cycle and cause growth arrest and apoptosis [6] 

Prevalence of p53 Alterations in Human Cancers

The p53 gene is the gene is associated with large number cancers. It is an important tumour suppressor and has biological properties which affect the cell proliferation. It is a nuclear phosphoprotein which is a produced by TP53 gene. This gene is known as tumour-suppressor gene and is mutated in about half of almost all types of cancer [7] . It is a type of cancer gene that is created by loss-of function mutations in a cell. The p53 protein functions are an integral part of cellular signals and then acts as a central link in a signal transduction network that responds to minimal mutations and other errors that can lead to cancers or other pathologies [8] . The activating mutations in oncogenes that generate oncogenic alleles from proto-oncogene precursors can also activate tumour suppressor genes, and the proteins they encode, are functionally inactivated by mutations which can lead to proliferation abnormalities. Among the genes which can be induced by p53 are the Cdk inhibitor, p21Cip1 and many other genes encoding proapoptotic proteins. The p53 negative regulator Mdm2 that plays a role in terminating the p53 response. Mdm2 binds directly to p53 to inhibit transcription, and it catalyzes p53 ubiquitination, targeting p53 for degradation. [9] It also been shown that p19Arf binds directly to Mdm2 to antagonize these functions [10] . Mutations in other genes that affect p53 includes are mutations affecting Hdm2, ARF, and a series of transcription factors that control ARF and p53 gene expression [11] 

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Activators of p53 and the subsequent pathways

Biological Properties of p53

The Biological properties of p53 gene and protein statuses both play a key role in the regulation of the cell cycle, cell cycle arrest, and apoptotic response [12] , [13] , [14] . p53 can be activated by various factors include lack of substrate like nucleotide, Ultra violet radiation, ionizing radiation, oncogenic signalling, hypoxia and blockage of transcription factors. In initial responses, cellular changes the half-life of the p53 protein which leads to accumulation of p53 in stressed cells. This causes significant changes in cell forcing p53 to be activated as a transcription regulator in these cells. Abrogation of p53 function can extend the replicative lifespan of human primary cells. Its levels are kept low through a continuous degradation of p53 in an unstressed cell via Mdm2, which is itself is a product of p53. It binds to p53, preventing it from its action and transporting it from the nucleus to the cytosol. Mdm2 also acts as ubiquitin ligase which covalently attaches ubiquitin to p53 and thus marking p53 for degradation by the proteasome. However, ubiquitylation of p53 is a reversible process. Deubiquitylating enzyme that cleaves ubiquitin from its substrates like USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one way by which p53 is stabilized in response to oncogenic insults. It acts on cell cycle, proliferation and angiogenesis by various pathways few of them are described below.

Cell cycle inhibitors

P53 plays a central role in the induction of apoptosis and cell-cycle arrest. It is one of the most important checkpoint proteins of cell survival and genomic integrity, which can be induced by a variety of different cellular damage & stimuli like DNA damage, oncogenic or hypoxic stress. [15] Once the p53 is activated it binds to DNA and activates expression of several genes which encodes for p21. One of these genes includes WAF1/CIP1 which binds to the G1-S/CDK (CDK2) and S/CDK complexes inhibiting their activity. These molecules are important for the G1phase & S phase transition in the cell cycle. When p21(WAF1) is complexed with CDK2 the cell cannot continue to complete cell division. When there is a mutation it will no longer bind DNA in an effective way, as a consequence, the p21 protein will loose its inhibitory property for cell division. This will allow cells to divide uncontrollably and will cause neoplasia. [16] Another way through which it works is suppression of EZH2 expression, which is a novel pathway that contributes to p53-mediated G2/M arrest [17] . There are other links which can influence the cell proliferation one of these is via interlinking with Retinoblastoma gene pathway. Deregulation of E2F to induce ARF transcription provides one connection between the RB pathway and p53 [18] , [19] and may help to explain why most tumours have defects in the p53 pathway. Overexpression of E2F in established cell lines lacking ARF or p53 can enforce S phase entry even in the absence of mitogenic stimulation. [20] , [21] , [22] For instance in non-immortal human diploid fibroblasts instead undergo an ARF-dependent p53 response leading to G1 phase arrest and, later, to apoptosis. [23] 

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Interlinking pathways of p53, E2F , CDK, MDM2, ARF & pRB. [24] 

Copyright © 2010, The American Society for Clinical Investigation.

P53 & DNA repair

The p53 can acts and sense different pathways which are involve in DNA damage and repair. Phosphorylation of the N-terminal end of p53 by the protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional co activators, like p300 or PCAF, which then acetylates the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis. [25] Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity. In a similar manner Jade1 can stabilize pVHL which can stabilize and activate p53. Jade1 is the product of the von Hippel-Lindau tumor suppressor gene. [26] 

Slack A et al. PNAS 2005;102:731-736

P53 & transcription factors

p53 can induce apoptosis via transcription-dependent and transcription-independent functions. [27] It has ability to activate transcription, from promoters containing p53 response elements. [28] , [29] There are a number of p53 target genes that have been identified, including GADD45, mdm2 , p21/WAF1 , cyclin G , bax and IGFBP3 [30] , [31] , [32] , [33] , [34] , [35] . p53 mediates its anti-proliferative response via transcriptional activation of pro-apoptotic target genes, such as BAX and PUMA, and trans-repression of pro-survival proteins. Many tumours overproduce MDM2 to impair p53 function. p53 is activated upon cellular stress such as DNA damage and the presence of oncogenes. SMAD4 family is involved in signals from the cell surface to the nucleus that are activated by TGF-β, hence leading to inhibition of cell proliferation. SMAD family can activates p21 & p27 which in turn can affect the functions of CDK2 and cyclin E which can alter cell proliferation. Also to note that p53 produces P21 that has the same action as P16 in inhibiting the action of cdk4/cyclin D

P53 & angiogenesis

Tumourogenesis is associated with angiogenesis; mutations in TP53 are associated with an increase in tumor angiogenesis [36] , [37] . It has been shown that hypoxia can alter the expression of miRNA and that miRNA can alter HIF-1α expression in vitro [38] ,. Recent evidence suggests that antiangiogenic therapy is sensitive to p53 status in tumors, implicating a role for p53 in the regulation of angiogenesis. Studies have shown that p53 transcriptionally activates the α(II) collagen prolyl-4-hydroxylase [α(II)PH] gene, which can release antiangiogenic fragments of collagen type 4 and 18 in extracellular matrix. This transformed media from cells ectopically expressing either p53 or α(II)PH can inhibit growth of primary human endothelial cells. Similar thing when happens either intracellularly or exogenously delivered, α(II)PH significantly inhibits tumour growth. This shows a genetic and biochemical linkage between the p53 tumour suppressor pathway and the synthesis of antiangiogenic collagen fragments. [39] , [40] 

HIF and p53 (Kim J et al. J Exp Med 2004; 199:113-124)

p53 targeted Therapies

In p53 mutated cells activation of p53, can potentially be achieved through genetic or pharmacologic methods and it can directly induce apoptosis and re-establish responses to cytotoxic drugs , if there is any defect in these checkpoint it can not only promote tumour development, but also contribute to multidrug resistance. Development of selective inhibitors of these pathways has long been underway, and many are already in clinical trials for cancer treatment. Cdk inhibitors , , might also prove useful in treating tumours that overexpress cyclin D1-Cdk4 or that have lost INK4a function. Its association with angiogenesis, increased hypoxic signalling may be more susceptible to antiangiogenic therapy than tumors with an intact p53 pathway. , There are various achievements, which have shown promising results in targeting the p53 genes including vaccines. [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] 

Conclusion

Hence p53 is an important protein secreted by TP53 gene and it works as a strong factor in antiproliferative pathway. It acts, direct or indirect way to attain the balance in cells life. If there is a loss of p53 function it can promote cancer. The advancement in the field there is hope that we can block this by the use of these specific inhibitors to get back the functions of p53. In this way we can make our way forward in reducing the side effects and enhance the efficacy of treatment.