P53

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Image:P53.png
p53 (blue) bound to a short DNA fragment (orange); zinc ions (green). Based on PDB id 1TUP.
tumor protein p53
Identifiers
Symbol(s)	TP53
Entrez	7157
OMIM	191170
RefSeq	NM_000546
UniProt	P04637
Other data
Locus	Chr. 17 p13.1

The correct title of this article is p53. The initial letter is shown capitalized due to technical restrictions.

p53, also known as tumor protein 53 (TP53), is a transcription factor 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" or the "master watchman", referring to its role in conserving stability by preventing genome mutation.<ref>Strachan T, Read AP. (1999). Human Molecular Genetics 2. Ch. 18, Cancer Genetics</ref> The name is due to its molecular mass: it runs as a 53 kilodalton (kDa) protein on SDS-PAGE.

1 Names
2 Gene
3 Structure
4 Functional significance
5 Role in disease
6 History
7 See also
8 References
9 External links

[edit] Names

Official protein name: Cellular tumor antigen p53

Synonyms:

Tumor suppressor p53
Phosphoprotein p53
Antigen NY-CO-13

[edit] Gene

The human gene that codes for p53 is TP53. The gene is named TP53 after the protein it codes for (TP53 is another name for p53). Italics are used to distinguish the TP53 gene name from the TP53 protein name. The gene is located on the human chromosome 17 (17p13.1).

The location has also been mapped on other model animals:

Mouse - chromosome 11
Rat - chromosome 10
Dog - chromosome 5
Pig - chromosome 12

[edit] Structure

Human p53 is 393 amino acids long and has three domains:

An N-terminal transcription-activation domain (TAD), which activates transcription factors
A central DNA-binding core domain (DBD). Contains zinc molecules and Arginine Amino Acid Residues.
A C-terminal homo-oligomerisation domain (OD). Tetramerization greatly increases the activity of p53 in vivo.

Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53.

Wild-type p53 is a labile protein, comprising folded and unstructured regions which function in a synergistic manner.<ref>Bell S, Klein C, Muller L, Hansen S, Buchner J (2002) p53 contains large unstructured regions in its native state. J Mol Biol. 2002 Oct 4; 322(5): 917-27; Abstract</ref>

[edit] Functional significance

p53 has many anti-cancer mechanisms:

It can activate DNA repair proteins when DNA has sustained damage.
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 irreparable.

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 MDM2, which prevents its action and promotes its degradation by acting as ubiquitin ligase. 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 or within the MDM2-binding region and p300-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 transcribes several genes including one for p21. p21 binds to the G1-S/CDK and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. p53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis ^[7].

Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.<ref>Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH (1998) p14ARF links the tumour suppressors RB and p53. Nature. 1998 Sep 10; 395(6698): 124-5; Entrez PubMed 9744267</ref>

[edit] Role in disease

If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome. The TP53 gene 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 TP53 gene.

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, the Human papillomavirus (HPV), encodes for a protein, E6, which binds the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, p105RB, allows for repeated cell division manifestested in the clinical disease of warts.

In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop MDM2 is itself induced by the p53 protein. However mutant p53 proteins often don't induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels^[4].

[edit] History

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. The TP53 gene was first cloned in 1983 by Moshe Oren (Weizmann Institute).

It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989 by Bert Vogelstein working at Johns Hopkins School of Medicine.

In 1993, p53 was voted molecule of the year by Science magazine.

[edit] See also

[edit] References

[edit] External links

Cell signaling
Key concepts - Ligand \| Receptor \| Second messenger \| Protein kinase \| Transcription factor \| Cell signaling networks
Pathways - Apoptosis \| Ca²⁺ signaling \| Cytokine signaling \| Hedgehog \| Integrin signaling \| JAK/STAT \| Lipid signaling \| MAPK/ERK pathway \| mTOR \| NF-kB \| Notch \| p53 \| TGFβ \| Wnt