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 P53 Signaling

The phosphoprotein p53 is a cell stress sensor molecule. P53 responds to stress factors that damage DNA, such as ionizing radiation, genotoxic drugs and free radicals. In normal cells, p53 functions as a key coordinator of DNA-damage cell-cycle check point activity. It stops DNA replication and facilitates DNA repair. When P53 is activated it drives the expression of proteins involved in DNA repair, cell-cycle arrest, redox regulation, protein degradation and apoptosis. Depending upon the cell type and context, p53 is an effective promoter of apoptosis, primarily, but not exclusively, via activation of mitochondrial apoptotic machinery (Noxa, PUMA, Bax, p53AIP1). The effects of p53 are limited primarily by mouse double minute 2 (mdm2) protein. P53 is activated by various kinases such as casein kinase 2 (CK2/CSNK), DNA-PK or ataxia-telangiecstasia mutated (ATM)-associated protein kinase (Box 1 motif). At least seven negative and three positive feedback loops affecting p53 activity are recognized. Six act through the MDM-2 protein to regulate p53 activity. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene products. In addition to MDM-2, there are two other ubiquitin ligases that can regulate p53 in an autoregulatory manner: Cop-1 and Pirh-2.

P53 is recognized as tumor suppressor protein p53 because it plays a critical role in the suppression of tumors exposed to irradiation and genotoxic chemicals. The p53 gene is mutated in over 50% of all human cancers. Most of the mutations in p53 associated with cancers map to the central core sequence specific DNA binding domain or the C-terminal tetramerization domain. Mutations in these domains inhibit the ability of p53 to bind DNA and activate specific genes or to assume a fully competent tetrameric transcription factor structure, respectively. Mutations in P53 can accumulate in cells under oncogenic pressure.