p53: Guardian of the genome?
Introduction
p53: what does it do?
The links to cancer
The Li-Fraumeni Syndrome
Conclusion
Introduction:-
Genes regulating growth and proliferation of cells were considered prime targets for mutational changes and other modification leading to cancer, earlier on in the study of the pathogenesis of cancer. The fact that inactivation rather than abnormal activation of a gene could lead to cancer was not thought by many, to be of any consequence. The first step in this direction was taken, probably by Knudson, when he proposed the now-famous "two-hit" hypothesis for the origin of sporadic and inherited retinoblastoma. Looking back today, it may seem surprising that an obvious fact, as to two copies of the gene whose function is fundamentally inhibitory in nature should be deleted for any phenotypical changes to seen, was failed to be appreciated. An elaborate set of 'rules' and conditions are stated to explain the hypothesis even today. p53 is a similar to the retinoblastoma gene, Rb (formerly known as p110RB1 ) in this aspect that loss of heterozygosity is essential the intiation of the carcinogeneic process.
p53: What does it do?
:- p53 is a gene on 17q. It's protien product is one of M.W 53,000, thus the name for the gene and the protien. The protien is intra-nuclear in location and it undergoes phosphorylation/dephosphorylation cycles as a part of it's functioning. The important point here, is that p53 is in no way required for normal progression of the cell division cycle. That is to say, in a perfect cell where no DNA damage and DNA mutations take place, p53 is not needed. But no cell can stake claim to such luxury and so p53 is needed.
Levels of p53 protien seem to determine the cell's entry into the 'S' phase. Excessive DNA damage in some way triggers the transcription of the p53 gene leading to increased levels of the p53 product. The increased levels of p53 either halts cell cycle progression ( by induction of p21 mediated inhibition of cyclin dependant kinase activity) or initiates apoptosis, if the damage to the DNA is too great. It is for this reason that p53 is often called the "guardian of the genome", "the molecular policeman", "guardian of the G1 checkpoint". Since the G1 phase of the cell cycle is the phase where the 'readiness of a cell to commit to replication' is determined, it is not surprising that a heavyweight as p53 should be sitting at the exit point of G1!
The links to cancer:
- Mutations in p53 are the most common among the genetic alterations seen in the solid tumours. Upto 50 percent of tumours show p53 changes. Deletion of one of the gene on chromosome 17p and mutation of the other is the most frequent among these changes.
- Approximately 100 different mutations are seen in the p53 gene in cancers and the mutations are usually in the highly conserved codons.
- Transistions( a purine-for-a-purine substitution, a pyrimidine-fo-a-pyrimidine substitution) occuring in the CgP dinucleotides are a source of spontaneous mutations in the p53 gene. These are frequently implicated in neoplasms of the colon, brain and the lymphoid tissue.
- Transversion( a purine-for-a-pyrimidine change) are assosciated with hepatocellular carcinoma. The biological carcinogen Aflatoxin B1 is said to cause a G-T transversion at codon 249 in cases of hepatocellular carcinoma. Demonstration of a certain genetic sequence change brought about in vitro by a chemical substance and subsequent demonstration of the same change in persons exposed to high levels of the same or a different compound provides us a sound basis for the recognition of carcinogens, as it was proved in the case of Aflatoxin B1
- The loss of function mutations of the p53 region usually involve the region of the gene between codons 120 and 290, the exon-rich region of the gene.
- Certain tumour causing viruses 'use' p53 to produce their effects. The E6 protien of the papilloma virus reduces p53 half life; p53 fails to accumulate in suffcient levels in cells with DNA damage and cell cycle control is lost in these cells. Other viral protiens like the E1B of an adenovirus and the large T antigen of the SV40 virus form inactivating 1:1 dimeric complexes with p53 molecules and thus manifest their effects.
The Li-Fraumeni Syndrome:-
Germline mutations are seen in the p53 gene at locus 17q13 in the Li-Fraumeni syndrome. This syndrome is often considered the analog of retinoblastoma for the p53 gene. Affected individuals have a propensity to develop a wide variety of cancers including breast cancers, lymphomas, osteosarcomas and a variety of other neoplasms and they die at a young age. The mutations frequently involve the codon 252. Li-Fraumeni is an example to the exceedingly importance of p53 in normal cell division, mutations are seen in an alarming rate in the absence of p53 function.
Conclusion:-
Genes like p53, Rb could well represent weak links in the regulation of the normal cell cycle progression. The number of mutations in p53 causing loss/altered function in the gene stand testimony to the fact that, the whole regulatory process remains susceptible to certain individual gene products and their function. Despite the hallowed function of molecular policing in the normal setting, p53 mutations are the most commonly encountered mutations in tumours.