p53 and its Isoforms: Implications on Cellular Processes

TP53 or p53 is a tumour suppressor protein rightly termed as the 'Guardian of the genome'. Various isoforms of p53 exist and have different roles in cellular processes.

Isoforms of p53 in Cellular Processes

Highlights

  • p53 is a Guardian of the genome
  • p53 has 12 isoforms
  • p53 isoforms are involved in various diseases

Guardian of the Genome

p53 (also known as TP53 or tumor protein, EC :2.7. 1.37) is a tumour suppressor protein rightly termed as the 'Guardian of the genome'. It coordinates several cellular processes involving cell death and proliferation. Upon different stress signals p53 gets activated, thereby initiating transcription of p53 responsive genes and ultimately triggering the p53 pathway (Figure 1). Because it controls many cell-fate-deciding genes, p53 has a prominent role in cancer—both for the diagnosis and the treatment. In more than 50% of the cancers p53 is mutated which majorly contributes to cancer progression. In simple words, the cells with DNA damage, whose normal fate is to die, can survive, divide irregularly, and cause cancer in absence of p53.

Activation of p53 pathway under different stress conditions
Figure 1: Activation of p53 pathway under different stress conditions

p53 Isoforms in Diseases

Other than point mutations, various isoforms of p53 can be also responsible for its inactivation. Using multiple promoters, alternative splicing and Internal ribosomal entry site (IRES) p53 gene can have 12 different isoforms of the protein (Figure 2).

p53 protein domains and region of synthesis of its different isoforms
Figure 2: p53 protein domains and region of synthesis of its different isoforms

It has been observed that the p53 isoforms are differentially expressed in normal and tumorigenic tissue in different types of cancer 2. Different reports have shown that cancer can occur despite a low mutation rate of TP53; in many such cases a significant change in the expression level of the p53 isoforms has been observed. There are reports of decrease in the expression of the p53 and p53 isoforms by 60% in breast cancer and an increase in the expression of ∆133p53 by 40%.  The same pattern is observable in acute myeloid leukaemia, where only 10% of the cases bear a mutation of p53, while a large shift in the expression level of the p53 and its isoforms can be observed. All these observations have opened new areas in cancer biology for understanding the role of p53 isoforms in disease manifestation. Some of the major roles played by the isoforms are listed below (Table 1).

Table 1: Some of the major roles played by the isoforms

p53 isoform

Reported cellular effect

FLp53β

Promotes senescence and is expressed in colon cancer, AML, Renal cell carcinoma etc. Reduced expression in breast cancer.

FLp53α

Overexpression leads to increased survival chances in AML patients. Good prognosis in breast cancer patients.

∆40p53

Induces cell death and tumour suppression, prolongs pluripotency in embryonic stem cells, role in glucose homeostasis and modulates p53 activity through direct binding to the protein.

∆133p53α

Pro-survival factor inhibits p53 dependent apoptosis and other transcriptional activity. Mostly found to be upregulated in cancers.

∆133p53β

Promotes epithelial to mesenchymal transition and enhances stemness in breast cancer cells.

∆160p53

Widely involved in oncogenic mutant p53 gain of function

 

Other functions of p53 isoforms

One of the most important isoforms of p53 is ∆40p53, which is the only translational isoform. Other than its several roles in cancer including tumour suppression and induction of cell death it has other functions as well. It induces pluripotency in ESCs and prevents them to get differentiated. Thus, it enhances stemness in the very early stages of life, however in adult stages it mostly regulates p53 functions. It is also known to decrease pancreatic β-cell proliferation and maintain glucose homeostasis. Another important isoform of p53 is ∆133p53β and it is known to have a pro-viral effect in Influenza virus infection enabling replication of the virus. It also contributes to H. pylori infections by inducing NFκB levels.

Keynotes

p53 in cancer has been widely studied however very few studies have investigated the role of its isoforms. Therefore, many ambiguities remain which needs to be investigated for better prognosis in cancer and other diseases. ∆40p53 is known to form heterotetramers with p53 and regulate the cell fate. However similar studies need to be done for other isoforms which shows a more pro-survival phenotype and might lead to a more resistant cancer. Understanding the principles of the p53 isoforms will not only enrich our knowledge but might also help in prognosis and treatment in cancer.

Schematic of p53 function
Figure 3: Schematic of p53 functions

 

Journal References

1. Aubrey, B., Kelly, G., Janic, A. et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?. Cell Death Differ 25, 104–113 (2018). https://doi.org/10.1038/cdd.2017.169

2. Vieler, Maximilian, and Suparna Sanyal. “p53 Isoforms and Their Implications in Cancer.” Cancers vol. 10,9 288. 25 Aug. 2018, doi:10.3390/cancers10090288