THE RELATION BETWEEN P53 AND CANCER
P53 is a transcription factor that is activated by DNA damage to switch on the expression of various genes (Figs. 1, 2).
These protect cells against DNA damage by stopping the cell cycle and division until the damaged DNA has been repaired, or by killing the cell, the precise effect depending on the specific genes activated by p53 (Fig. 3).
3. p53 in cell cycle control.
The cell machinery that detects DNA damage is exquisitely sensitive: it can pick up just one break in the two metres of double-stranded DNA in each cell and as a result turn on the P53 gene. One target of p53 is a gene that controls cell cycle arrest, WAF1 (wild-type p53-activated fragment 1), by encoding a protein that blocks the action of several of the kinases that drive the cycle – so it’s a cyclin-dependent kinase inhibitor (CKI). This buys time for DNA repair systems to rectify DNA damage, whether the mutations have been caused by UV light or by other mutagens.
Simply giving the cell more time may not be enough, however. When damage occurs the best anti-cancer tactic is to destroy the cell and a second critical role of p53 is as an activator of apoptosis, the controlled programme by which cells commit suicide. Among its targets are three genes, BAX, PUMA and NOXA, that stimulate apoptosis by permeabilising the outer mitochondrial membrane. This releases pro-apoptotic proteins, in particular, the respiratory chain component cytochrome c, which activates the cell death programme. p53 has switched on the most effective cancer protection you could have – the elimination of a cell that is likely to turn into a tumour precursor.
We saw earlier that MYC is essential for cell proliferation and that it is often deregulated in cancer, leading to hyper-proliferation that, in turn, can increase genetic instability and promote tumorigenesis. By way of contrast, MYC can also exert tumour suppressor effects that result in either apoptosis or senescence. This remarkable duality reflects the role of MYC stress responses that, in normal cells, leading to cell death. One action of MYC that induces apoptosis is the suppression of WAF1 transcription: this prevents cell cycle arrest and switches p53 to the activation of apoptotic mediators (BAX, PUMA and NOXA). In addition, MYC also inhibits expression of anti-apoptotic genes in the BCL2 family.
Thus in normal cells, low levels of MYC expression are required for growth and division high concentrations confer protection to stress by initiating cell death. However, if cells lose a critical component of the tumour suppressor network, particularly p53, elevated MYC activity becomes a powerful tumourigenesis driver.
The critical role of p53 led David Lane to describe it as ‘guardian of the genome’. As cancers almost always involve disruption of the genome it is unsurprising that P53 is one of the most frequently mutated of all cancer genes. P53 is on chromosome 17 in a region that is often deleted in human cancers but, in addition to the complete loss of the gene, over 6,000 P53 mutations have been detected. All told, over 70% of human cancers have a mutation that affects the activity of p53. Mutations are usually somatic (not inherited) and occur with high frequency in all types of lung cancer, in over 60% of breast tumours and in ~40% of brain tumours (astrocytomas), frequently in combination with the activation of oncogenes. P53 provides a good example of how a specific effect of a carcinogen can promote cancer. Studies of the X-ray crystallographic structure of p53 complexed with DNA reveal that there are several mutational hotspots at amino acids that directly contact DNA and are therefore critical for its function as a transcription factor (Fig. 4.21). Guanine residues in these codons react with a specific component of cigarette smoke (benzo[a]pyrene), which makes this polycyclic aromatic hydrocarbon a potent mutagen and carcinogen.
Although most P53 mutations are somatic, some unfortunate individuals inherit one defective allele, as can happen in retinoblastoma with RB1. This gives rise to the rare, autosomal dominant disease Li-Fraumeni syndrome: 50% of the carriers develop diverse cancers by 30 years of age, compared with 1% in the normal population.