Not everyone in this world has cancer. There are people who are pretty much vegan, some even don’t smoke or drink, some are more physically active, but still when an individual of aforementioned lifestyle gets cancer, then scientist try to wonder the reason behind it.
So what is exactly happening then?
Years of research has brought in the knowledge and understanding of certain molecular entities within the cell which play a major role in preventing cancer. Of all these molecules, p53 is one of them.
So what is p53?
Tumor suppressor p53 is a protein encoded by the gene TP53. The protein p53 is known for its role in maintaining the stability of the genome whilst not allowing mutation. TP53 gene is located on the short arm of chromosome 17. The gene spans to a size of 20kb wherein, non-coding exon comprise of 1kb and long intron comprise of 10kb.
How exactly p53 helps and/or functions?
Protein p53 has two functions, it suppress the growth of cells and also provides support for apoptosis.
As the name itself suggests, p53 being tumor suppressor play an important role in the protection of body from cancer. Inside the cell, p53 protein binds to DNA, stimulating another gene to produce protein p21. p21 interacts with a cell-division stimulating protein (cdk2). When p21 gets complexed with cdk2, the process of cell division is interrupted such that the cell can’t pass through the next stage of cell division (specifically S phase). Similarly, p53 proteins bind to DNA, producing proteins like GADD45 and14-3-3-σ. Both these proteins further go onto stimulate another cell division stimulating protein (cdc2), which arrest cell division (specifically at M phase) as shown in the figure above.
Support for apoptosis:
Apoptosis is the process of programmed cell death which mostly occurs in multi-cellular living organism. The video below will give a more brief understanding about apoptosis:
Role of p53 in regulating apoptosis is shown in the video below:
What happens when p53 gene malfunctions?
When a person inherits only one functional copy of p53 gene from parents, they are predisposed to cancer and develop independent tumors in variety of issues in early adulthood. In most tumor types p53 mutations are found, contributing to the complex network molecular events leading to tumor formation. When mutation occurs on p53 gene, it can no longer bind to DNA effectively. As a result the protein p21 isn’t made available which can act as a stop signal for cell division. Thereby, the cells divide uncontrollably and form tumors.
What Regulates p53?
From the early days of p53 research, scientists knew that, in normal unstressed cells, p53 protein is scant, and that its turnover is rapid. Mdm2 was discovered in 1992 to bind to, and negatively regulate, transactivation by p53, and was then itself found to be a transcriptional target of p53, defining a negative feedback loop (Momand et al. 1992, Picksley & Lane 1993). Accordingly, the embryonic lethality of Mdm2 knockout mice could be rescued by knockout of p53 (de Rozieres et al. 2000). Later studies revealed a similarly important role for MdmX, an Mdm2 homolog (Shvarts et al. 1996). Mdm2 proved to be an E3 ubiquitin ligase, stimulating p53 degradation (Haupt et al. 1997, Honda et al. 1997, Kubbutat et al. 1997). It is now recognized that the action of ubiquitinases and deubiquitinases determines the activity of the p53 network. These findings explain the relatively high levels of p53 in tumors, as p53 mutants are transcriptionally inert, disrupting the feedback loop.
Is p53 Chemically Modified in the Cell?
The p53 protein is not active in the cell unless it is first modified by other proteins. In other words, the actual mass of p53 is not as important as the amount of activated p53, and only activated p53 can bind to DNA and stimulate the expression of its target genes. Although it was known since the 1980’s that p53 levels increase after irradiation, only in 1992 was p53 shown to be regulated by ATM; a kinase orchestrating the DNA damage response (Banin et al. 1998, Canman et al. 1998). The p53 protein was subsequently demonstrated to be phosphorylated after DNA damage, and was the first non-histone protein shown to be acetylated by p300/CBP (Ionov et al. 2004). Biochemical studies showed DNA damage inducible kinases such as ATM (Westphal 1997) and Chk2 (Tominaga et al. 1999, Shieh et al. 2000) can phosphorylate key p53 residues that regulate its binding to Mdm2 and p300/CBP. The alternative reading frame (ARF) protein, known to be induced by a number of mitogens, was also shown to block the ability of Mdm2 to degrade p53, thereby linking p53 to key oncogenic pathways (Kamijo et al. 1998). The p53 protein has been shown to bind to dozens of other proteins, explaining its involvement in a wide range of physiologic processes.
What is the Future of p53 Research?
Although there have been tens of thousands of publications on p53, much is still unknown (as shown in figure below). We still do not understand the microenvironmental conditions that favor the selection of cells with p53 mutations. Is the stimulus continuous or unrepairable DNA damage? Or is it perhaps reactive oxygen species, in association with alternating cycles of hypoxia and normoxia? In similar fashion, we don’t yet understand why the expression of wt p53 results in apoptosis in some cells and cell cycle arrest in others, nor how the various post-translational modifications of p53 are related to this switch.
And perhaps most importantly, we don’t yet know how to use the immense amount of knowledge so far gained about p53 for therapeutic purposes. Clever approaches to achieve this goal — small molecular weight compounds or peptides that reactivate mutant p53 or disrupt the interactions between MDM2 and wt p53, or viruses that only replicate in cells without a functional p53 network — have been developed and show great promise. However, the field is wide open to new, creative approaches that target p53, a protein that is inactivated in the majority of human cancers. History shows that the most novel ideas — the really bold and creative ones — often come from students.