p53: The silent warrior against cancer !!!


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.

intro2Schematic diagram showing how p53 helps in growth arrest

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.


Biomarkers: The future medicine !!!!


Biomarkers are key molecular or cellular forms linking specific environmental exposure to a health outcome. Biomarkers give a better understanding towards the relationship between exposure to the environment chemicals and initial stages of development of chronic human diseases. New research has helped in identifying and validating new biomarkers to be used in population based studies of environmental disease. Biomarkers form an indispensable part of personalized healthcare, but, the spectrum of biomarker cases and purposes is broad.

The main uses of biomarkers include:

  • Measuring wellbeing and health, both physical and mental;
  • Assessing disease susceptibility and risk;
  • Grading disease severity;
  • Predicting outcomes;
  • Determining the optimal type of intervention, treatment, nutrition and so on;
  • Evaluating response to therapies;
  • Monitoring compliance;
  • Forensic applications.

In developing a viable biomarker the primary consideration is to match the intended purpose with robustness, ease of use and sensitivity/specificity. Biomarkers used in predictions typically should involve substrates that are relatively stable over time. Types of biomarkers vary depending upon its use. Perera and Weinstein classified biomarkers based on the sequence of events from exposure to disease as shown in figure below. 


Blood is one of the simplest biomarkers found in human body. Recent research has revealed the extent of using blood as a biomarker for diagnosing early onset of Alzheimer’s disease.

Genetic biomarkers are slowly gaining ground in research with this latest one on differentiating alzheimers disease and dementia with lewy bodies.

The recent research has shown the future of biomarkers with respect to early diagnosis in medicine. A new blood biomarker analysis has been demonstrated to predict short term mortality. Based on measurable biomarker patients are assigned to risk groups, estimating the risk of dying within next five years as compared to multifold with respect to general population. Engineers from Massachusetts Institute of Technology (MA, USA) have developed a simple and cheap paper test that aims to improve cancer detection rates, particularly in developing countries. The test works in line with that of pregnancy test can predict whether a person has a cancer using urine sample.

Your saliva protects you from cancer !!!!!

ImageResearchers at John Hopkins Kimmel Cancer Center(2) have found a compound in saliva, which along with common proteins in blood and muscle may protect human cells from toxins in tea, coffee and liquid smoke flavoring. The article cited in Food and Chemical Toxicology(1) journal, suggest that humans can naturally launch multiple defenses against plant chemicals called pyrogallol like polyphenols or PLPs found in tea, coffee, and liquid smoke flavoring. The presence of these natural defenses in people explains why PLPs are not crippling cells and causing illness, as expected from their widespread use.

Johns Hopkins Investigator Scot Kern, M.D., and his colleagues showed that PLPs found in everyday food and flavorings could do significant damage, by breaking strands of DNA. At some stage the damage caused by these toxins (PLPs) were found to be 20 times more than that of chemotherapy drugs, which are used for cancer patients. Baffled by these developments, researcher thought to find out why there was no further damage and how these cells are fighting them back. Kern said, “If these chemicals are so widespread–they’re in flavorings, tea, coffee–and they damage DNA to such a high degree,” adding further, “we thought there must be defense mechanisms that protect us on a daily basis from plants we choose to eat.”

An enzyme in saliva called alpha-amylase, along with the blood protein albumin and muscle cell protein myoglobin, together protected cells from DNA breakage by tea, coffee and isolated PLPs. Researchers measured DNA damage by looking onto the activity levels of p53 gene. A gene that helps in repairing damaged DNA. “It was quite easy to uncover a few of these protective substances against the tested cancer therapeutic drugs, which suggests there may be many more layers of defenses against toxins,” said Kern, the Kovler Professor of Oncology and Pathology at the Johns Hopkins University School of Medicine.

It was also found that the saliva enzyme and the proteins did not protect against the chemotherapeutic drugs, which can also damage DNA. This clarifies the fact that, defenses against PLPs may have evolved against a response to natural plant compounds, which is a part of human diet for a long time. Surprisingly, cells did not seem to need these protector proteins after a period of exposure to the toxins. Kern further explains, “After about two weeks we found it difficult to get the cells to be damaged by the same chemicals, even if they were damaged by the chemicals weeks earlier.” He further adds, “They seem to have some innate ability to respond to the damage or sense it and somehow protect themselves against it, even in the absence of albumin, muscle proteins or saliva components.” “It made us wonder, do people who eat the same PLP-containing diet day after day develop a natural cellular protection to the toxins,” Kern asked, “so that, as has been said before, what doesn’t kill us makes us stronger?”

Researchers are planning further, to study how albumin, myoglobin and salivary alpha-amylase protect against PLPs and their possible innate defenses against the chemicals. Kern also plans an alternative study, to find how these natural defenses were compromised in some people causing cancers or other illnesses. Finding of the research also speculates that a morning cup of coffee might be less harmful if enjoyed with a protective myoglobin from a meat (chicken, bacon, etc…). Also eating smoked meat might be less toxic if they are enough to make you salivate. But researchers say that these ideas are just speculation.


 1) Scott E. Kern, M. Zulfiquer Hossain, Kalpesh Patel, , 2014. Salivary α-amylase, serum albumin, and myoglobin protect against DNA-damaging activities of ingested dietary agents in vitro. Food and Chemical Toxicology, Volume 70, Pages 114–119.

 2) Hopkinsmedicine.org. 2014. Compounds in Saliva and Common Body Proteins May Fend Off DNA-Damaging Chemicals in Tea, Coffee and Liquid Smoke.[Accessed 23 June 14].