Structure and Function of the P53 as a Tumor Suppressor

Tumor Suppressor p53
The p53 tumor suppressor, also known as the TP 53 or tumor protein can be referred to as a gene that codes for a protein that is responsible for the regulation of the cycle of the cell and therefore acting as tumor suppression. It is significant for cells in multicellular organisms to suppress cancer, p53 has been referred to as ‘the guardian of the genome’ as extracted from its role in the conservation of the stability by hindering the mutation of the genome. The name p53 comes from the molecular mass that it has-53 kilodalton fraction of the cell proteins.
The research conceited with the cure for cancer and its management dates many decades ago, but in 1979 there was a significant breakthrough. There were six groups of investigators each working separately and independent of each other came to an amazing similar discovery of a 53 kDa protein that was seen to be inherent in the mouse cells and the human cells. Among these studies, five of them discovered the protein because it was bound to the T-antigen in SV40 infected cells hence was immunoprecipitated with antibodies secreted against the viral protein. It was also discovered that the same protein was serendipitous when an antiserum generated against a chemically induced mouse sarcoma was seen to react with a 53 kDa protein present in transformed buy not normal mouse cells. Among the noted researchers noted are Arnold Levine, William Old and David Lane who identified the p53 identified it while working at Princeton University, Sloan-Ketterin Memorial Hospital and Dundee University (UK) respectively. Before then, it had been hypothesized to be in existence as the target of the SV 40, which was a strain that initiated development of tumors. Initially, it was thought to be an encogene but the true characteristics as a tumor suppressor gene was revealed in 1989. Come 1993, the p53 was historically voted as the molecule of the year by the science magazine, making it a great breakthrough in the cancer management globally (Nature Education, 2014).
The p53 structure
The p53 is widely known to be a phosphoprotein that is composed of 393 amino acids, it has four units otherwise referred to as domains. These four domains are; the domain that recognizes specific DNA sequences (core domain), the domain that activates transcription factors, the domain that takes care of the tretramerization of the protein and lastly the domain that recognize damaged DNA like the misaligned base pairs or single-stranded DNA. The wild-type p53 is categorized as the labile protein which is composed of the unstructured regions which function in a synergistic way.
The mechanism of the p53 is such that it plays a central role in the apoptosis and cell cycle control. It is noted that the defective p53 can facilitate the abnormal cells proliferation, resulting in cancer. It is also noted that a significant number of human tumors, indeed 50% of all human tumors contain p53 mutants. The evolution and change of a normal cell to cancerous cells is explained t be a complex process with various steps involving genetic and epigenetic alterations that give selective advantages on the altered cells. The tumerigenesis alterations are seen to give the evolving tumor with self-sufficiency of growth signals, evasion from programmed cell death, insensitivity to antigrowth signals, sustained angiogenesis, unlimited replicative potential and also the ability to invade the metastasize (Freed-Pastor W.A. & Prives C., 2017).
Though there has been massive research put into the research on the understanding of the cancer cells, though there have been impressive progress on the same over the past few decades, the full molecular understanding of the cancer still remains a big challenge to the biomedical community. In normal cells, the p53 protein level is known to be low, the DNA damage and other accompanying stress signals may activate the multiplication of p53 proteins and these p53 increased proteins have three main functions-to repair the DNA, growth arrest and apoptosis/cell death. The cell cycle progression is stopped by the growth arrest in effect hindering the replication of the damaged DNA. In the process of the growth arrest, the p53 may trigger the transcription of the proteins involved in DNA repair. Apoptosis is considered as the last resort which is meant to stop or prevent the proliferation of cells containing abnormal DNA.
It is important to note that the cellular concentration of p53 needs to be closely and tightly regulated since in as much as it can suppress the tumors, high levels of p53 may hasten the aging process by excessive apoptosis. Mdm2 is known to be one of the most effective regulators which is able to initiate the degradation of p53 through the system known as ubiquitin system. The regulation mechanism is illustrated in the below figure.

Mdm2 regulation mechanism as illustrated by Bioinformatics (2017)
There are target genes that the p53 target in hindering the cancer growth. P53 is said to be a transcriptional activator that regulate the expression of Mdm2 as well as the genes involved in growth arrest, apoptosis and the DNA repair. Some of those most important target genes are the p21, Gadd45 and 14-3-3s. which are responsible for growth arrest, p53R2 which is responsible for DNA repair and Bax, Apaf-1, PUMA and NoxA which are responsible for apoptosis.
Even though there is a large diversity in the genes responsible in tumorigenesis, the p53 transcription factor stands out as the major suppressor of tumors and the key regulator of various signaling pathways involved in this process. The TP53 mutations are said to take place in every type of cancer at different rates starting from the lowest of 10% for instance in hematopoietic malignancies and well close to 100% for instance in the high grade serous carcinoma of the ovary.
The other importance of p53 is when it cats as a cardinal player in protection against cancer development as seen emphasized by the Li-Fraumeni syndrome (LFS) which is a rare type of cancer predisposition syndrome that is linked with the germline TP53 mutations. However, the p53 tumor suppressor gene is different from the other tumor suppressor genes like the APC, RB and BRCA1 in that these are often inactivated as the cancer progresses through truncation mutations deletion, the TP 53 gene in human tumors is often found to undergo missense mutations in that a single nucleotide is substituted by another. The result of this process is a full-length protein that in it has a single amino acid produced.
The cancer associated TP53 mutations greatly vary in their locations within the p53 coding sequence as well as their effects on the thermodynamic stability of the p53 protein. It is noteworthy that a greater number of the mutations end up in loss of p53’s ability to bind DNA in a sequence-specific manner as well as the active transcription of canonical p53 target genes.
Mechanistic views of how mutant p53 exerts its function
Research has it that the p53 inactivation and mutant p53 expression can result in cells with survival advantage and additive growth like the evasion of apoptosis, increased proliferation as well as chemo-resistance. For a better understanding of the mechanism that underlie the role of mutant p53 at the different steps of tumor progression, it was significant to find out the animal models that express mutant p53in a controlled environment. As a matter of fact, the latest data obtained from the use of such in vivo models support the notion of GOF properties acquired by mutant p53 which drive cells towards invasion, metastasis and migration. In earlier research, it was found out that although the p53 knockout mice develop tumors at a higher frequency, they show low events of metastasis or invasive growth. On the contrary, mice knocked in with p53 R270H or R172H that corresponds to the human hotspot mutants p53R175H and p53R273H respectively developed highly metastatic tumors.
Additionally, recent study showed that the mutant p53 can help cell migration and invasion in in vitro assays. More significantly here is that the selection of oncogenic Tas and mutant p53 takes place in early neoplasms to augment growth and survival, they have a central role at late stages of tumor progression in empowering TGF?-induced metastasis.
Role of p53 in disease
In the event that the p53 is damaged, then the suppression of tumors is significantly reduced and people who inherit only one functional copy of p53 have a high likelihood of developing tumors in early adulthood, a disease referred to as Li-Fraumeni syndrome. The p53 has the possibility of being damaged in cells by mutagens such as the chemicals, viruses and radiation, hence increasing the likelihood that the cell will initiate uncontrolled division. And a matter of cat, more than 50% of human tumors has mutation or deletion of the p53 gene. For the body to be healthy, p53 is produced continually and degraded in the cell. The degradation of p53 is linked to the Mdm2 binding as discussed in the above section. Research indicates that in a negative feedback loop Mdm2 is itself induced by p53. However, the mutant p53s don’t often induce Mdm2 hence able to accumulate at very high concentrations. Even worse, the mutant p53 protein itself can inhibit p53.
Possible therapeutic use f p53
It is noted that the in vitro induction of the p53 in to the p53 deficient cells can cause rapid death of the cancer cells and/or prevent the continued division. The reasoning behind developing the therapeutic targeting p53 is that the most effective way of destroying network is to attack its most connected nodes. P53 is connected in a complex manner and simply knocking it out can cripple the normal operation of the cell. This can be considered as 50% of cancers have missense point mutations in the p53 gene, the mutations impair its anti-cancer gene initiating effects. Restoring its normal process of working or functioning would be a significant step managing many cancers (Hollstein M. and Harris C.C., 1993).
References
Bioinformatics (2017). Primary Information of p53. Retrieved November 24, 2017 from http://www.bioinformatics.org/p53/introduction.html
Hollstein M. and Harris C.C., (1993). Clinical Implications of the p53 Tumor-Suppressor Gene. Retrieved November 23, 2017 from http://www.nejm.org/doi/full/10.1056/NEJM199310283291807
Freed-Pastor W.A. & Prives C., (2017). Mutant p53: one name, many proteins. Retrieved November 23, 2017 from http://genesdev.cshlp.org/content/26/12/1268.full
Nature Education, (2014). p53 : The Most Frequently Altered Gene in Human Cancers. Retrieved November 24, 2017 from https://www.nature.com/scitable/topicpage/p53-the-most-frequently-altered-gene-in-14192717