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p53, also known as TP53 or tumor protein (EC: 184.108.40.206) is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppressor. It is very important for cells in multicellular organisms to suppress cancer. P53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation (Strachan and Read, 1999). The name is due to its molecular mass: it is in the 53 kilodalton fraction of cell proteins.
The human p53 gene is located on the seventeenth chromosome (17p13.1).
The location has also been mapped on other model animals:
- A domain that activates transcription factors.
- A domain that recognizes specific DNA sequences (core domain).
- A domain that is responsible for the tetramerization of the protein.
- A domain that recognized damaged DNA, such as misaligned base pairs or single-stranded DNA.
Wild-type p53 is a labile protein, comprising folded and unstructured regions which function in a synergistic manner (Bell et al. 2002).
p53 has many anti-cancer mechanisms:
- It can activate DNA repair proteins when it recognizes damaged DNA.
- It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition.
- It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irrepairable.
P53 is central to many of the cell's anti-cancer mechanisms. It can induce growth arrest, apoptosis and cell senescence. In normal cells p53 is usually inactive, bound to the protein MDM-2 , which prevents its action and promotes its degradation. Active p53 is induced after the effects of various cancer-causing agents such as UV radiation, oncogenes and some DNA-damaging drugs. DNA damage is sensed by 'checkpoints' in a cell's cycle, and causes proteins such as ATM, Chk1 and Chk2 to phosphorylate p53 at sites that are close to the MDM2-binding region of the protein. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity. Once activated p53 has many anticancer mechanisms, the best documented being its ability to bind to regions of DNA and activate the transcription of genes important in cell cycle inhibition, apoptosis, genetic stability, and inhibition of angiogenesis (Vogelstein et al, 2000).
Recent research has also linked the p53 and pRB tumour suppressor pathways, via the protein p14ARF, raising the possibility that the pathways may regulate each other (Bates et al, 1998).
Role in disease
If the p53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of p53 will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome. p53 can also be damaged in cells by mutagens (chemicals, radiation or viruses), increasing the likelihood that the cell will begin uncontrolled division. More than 50 percent of human tumors contain a mutation or deletion of the p53 gene.
In health p53 is continually produced and degraded in the cell. The degradation of p53 is, as mentioned, associated with MDM-2 binding. In a negative feedback loop MDM-2 is itself induced by p53. However mutant p53s often don't induce MDM-2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 (Blagosklonny, 2002).
Potential therapeutic use
In-vitro introduction of p53 in to p53-deficient cells has been shown to cause rapid death of cancer cells or prevention of further division. It is more these acute effects which hopes rest upon therapeutically (McCormick F, 2001). The rationale for developing therapeutics targeting p53 is that "the most effective way of destroying a network is to attack its most connected nodes". P53 is extremely well connected (in network terminology it is a hub) and knocking it out cripples the normal functioning of the cell. This can be seen as 50% of cancers have missense point mutations in the p53 gene, these mutations impair its anti-cancer gene inducing effects. Restoring its function would be a major step in curing many cancers (Vogelstein et al 2000).
Various strategies have been proposed to restore p53 function in cancer cells (Blagosklonny, 2002). A number of groups have found molecules which appear to restore proper tumour suppressor activity of p53 in vitro. These work by altering the conformation of mutant conformation of p53 back to an active form. So far, no molecules have shown to induce biological responses, but some may be lead compounds for more biologically active agents. A promising target for anti-cancer drugs is the molecular chaperone Hsp90, which interacts with p53 in vivo.
Adenoviruses rely on their host cells to replicate, they do this by secreting proteins which compel the host to replicate the viral DNA. Adenoviruses have been implicated in cancer-causing diseases, but in a twist it is now modified viruses which are being used in cancer therapy. ONYX-015 (dl1520, CI-1042) is a modified adenovirus which selectively replicates in p53-deficient cancer cells but not normal cells (Bischoff, 1996). It is modified from a virus that expresses the early region protein, E1B, which binds to and inactivates p53. P53 suppression is necessary for the virus to replicate. In the modified version of the virus E1B has been deleted. It was hoped that the viruses would select tumour cells, replicate and spread to other surrounding malignant tissue thus increasing distribution and efficacy. The cells which the adenovirus replicates in are lysed and so the tumour dies.
Preclinical trials using the ONYX-015 virus on mice were promising however clinical trials have been less so. No objective responses have been seen except when the virus was used in combination with chemotherapy (McCormick, 2001). This may be due to the discovery that E1B has been found to have other functions vital to the virus. Additionally its specificity has been undermined by findings showing that the virus is able replicate in some cells with wild-type p53. The failure of the virus to produce clinical benefits may in large part be due to extensive fibrotic tissue hindering virus distribution around the tumour (McCormick, 2001).
p53 was identified in 1979 by Arnold Levine ,David Lane and Lloyd Old , working at Princeton University, Imperial Cancer Research Fund (UK) and Sloan-Kettering Memorial Hospital , respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors.
- Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH. (1998) p14ARF links the tumour suppressors RB and p53. Nature 395:124-125
- Bell S, Klein C, Muller L, Hansen S, Buchner J. (2002). p53 contains large unstructured regions in its native state. J Mol Biol, 322:917-927
- Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F. (1996). An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science, 274:373-376
- Blagosklonny, MV. (2002). P53: An ubiquitous target of anticancer drugs. International Journal of Cancer, 98:161-166
- McCormick F. (2001). Cancer gene therapy: fringe or cutting edge? Nat Rev Cancer, 1:130-141
- Strachan T, Read AP. (1999). Human Molecular Genetics 2. Ch. 18, Cancer Genetics
- Vogelstein B, Lane D, Levine AJ. (2000). Surfing the p53 network. Nature, 408:307-310
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