Is Cancer a p53 Protein Aggregation or Prion Disease?

According to recent findings, P53 mutation can cause a conformational disease. A brazillian research team shows that p53 mutants can aggregate into prion-like amyloid oligomers and fibrils. The report states that under physiological conditions, the structure of central domain (p53c) which is made using sequence of wild type and the mutant R248Q aggregate into fibrils and amyloids.

The demonstration to prove the presence of the aggregates was done by using various techniques including electron microscopy, x-ray diffraction, FTIR, cell viability assays, dynamic light scattering and anti-amyloid immunoassays. The p53 aggregates were found in the nucleus of the tumor cell line that had p53 mutations and the seeding of a R248Q mutant with amuloid oligomers accelerated the aggregates formation. This shows that different rates of protein aggregation could explain the variability in different types of tumor cells.

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The protein p53 is vital for cell function as it suppresses tumor and regulates cellular responses to the genotoxic stresses. If there is only one functional copy of the p53 gene is present then the person is predisposed to cancer in early adulthood and generally develops independent tumors in different tissues.

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The p53 gene is located on the short arm of chromosome 17 and is encoded by TP53a mutation in p53 tumor suppressor is the most observed genetic alteration in human cancer. Most mutations result in a loss of DNA binding.

The p53 protein can be divided into seven domains:

1. One acidic N-terminal transcription-activation domain  or TAD, sometimes called activation domain 1 (AD1), that activates the factors of transcription.

2. An activation domain 2 (AD2) that is important for apoptotic activity.

3. A Proline rich domain also important for the apoptotic activity of p53.

4. The core DNA-binding domain (DBD) in the centre. This domain contains a single zinc atom as well as many arginine amino acids (residues 102-292). This domain is what binds the p53 co-repressor LMO3.

5. The domain that signals nuclear localization.

6. The homo-oligomerisation domain (OD). This domain is responsible for the tetramerization of the protein which is integral for p53’s activity of in vivo.

7. The C-terminal domain involved in down regulating the central DNA binding domain

The changes in p53 gene can also occur as germline mutations in some families with Li-Fraumeni syndrome. The activity of p53 can be regulated via post-translational modification such as methylation, phosphorylation and acetylation.

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