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p53 is a transcription factor that regulates the cell cycle and thus functions as a tumor suppressor. The human gene that encodes for p53 is TP53. It is located on the human chromosome 17p13.1.
Human p53 has five protein domains:
1. An N-terminal transcription-activation domain (TAD);
2. A proline-rich domain important for the apoptotic activity of p53;
3. A central DNA-binding core domain (DBD);
4. A homo-oligomerisation domain (OD) (tetramerization is essential for the activity of p53 in vivo);
5. A C-terminal domain involved in downregulation of DNA binding of the central domain.
Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations are recessive loss-of-function mutations that destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these gene. In addition, 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.
The anti-neoplastic activities of p53 involve: 1. activation of DNA repair mechanisms; 2. arrest of cell cycle at the G1/S regulation point following DNA damage recognition; and 3. initiation of apoptosis if cell recovery if the DNA damage proves to be irreparable.
In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stress, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will either induce a cell cycle arrest to allow repair and survival of the cell or apoptosis to discard the damage cell.
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 activates expression of several genes including one encoding for p21. p21 binds to the G1-CDK and S/CDK complexes, inhibiting the transition from G1 to S phase. p53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis. Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other
The critical event leading to the activation of p53 is the phosphorylation of its N-Terminal domain. The protein kinases which are known to target this transcriptional activation domain of p53, can roughly be divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc... A second group of protein kinases (ATR, ATM, Chk1, Chk2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress.