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p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell.
The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. [5] [6] In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. [5] [6] The expression of PUMA is regulated by the tumor suppressor p53.
Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53.
The absence of p21 or 14-3-3 cannot sufficiently inhibit the CyclinB-Cdc2 complex, thus exhibiting the regulatory control of p53 and p21 in the G2 checkpoint in response to DNA damage. [12] p53 mutations can result in a significant checkpoint deficit, which has important implications in the treatment of cancer.
Chk1/2 phosphorylate cdc25 which, in addition to being inhibited, is also sequestered in the cytoplasm by the 14-3-3 proteins. 14-3-3 are upregulated by p53, which, as previously mentioned, is activated by Chk1 and ATM/ATR. p53 also transactivates p21, and both p21 and the 14-3-3 in turn inhibit cyclin B-cdc2 complexes through the ...
The p53 protein is a transcription factor that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BAX. Wild-type p53 has been demonstrated to upregulate the transcription of a chimeric reporter plasmid utilizing the consensus promoter sequence of BAX approximately 50-fold over mutant p53.
P53 causes cells to enter apoptosis and disrupt further cell division therefore preventing that cell from becoming cancerous (16). In the majority of cancers it is the p53 pathway that has become mutated resulting in lack of ability to terminate dysfunctional cells.
One such example of the regulatory role that phosphorylation plays is the p53 tumor suppressor protein. The p53 protein is heavily regulated [28] and contains more than 18 different phosphorylation sites. Activation of p53 can lead to cell cycle arrest, which can be reversed under some circumstances, or apoptotic cell death. [29]