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Cancer arises through a series of mutations in selected oncogenes, tumor suppressor genes, or genes involved in DNA repair or replication. The tumor suppressor gene products frequently monitor the efficiency of cellular duplication by populating checkpoints in the process of cell division. When defective, the tumor suppressor genes can lead to inherited predispositions in the development of cancers...
The p53 tumor suppressor is one of the best studied human proteins. As described in this chapter, significant progress has been made towards understanding its three-dimensional structure. The structural information has helped our understanding of p53 function and regulation and has also explained how tumor-associated mutations inactivate p53. The challenge now is to extend the structural studies to...
The best-characterized function of p53, the most renowned tumor suppressor, is that of transcriptional activation. Upon its first description as a regulator of gene expression, p53 was simply thought to bind to an element within the 5′ UTR of a target gene, which would lead to transcription, by the appropriate machinery within the cell. Over the past 10 years however, this process has proven to be...
In addition to its well-characterized function as a sequence specific transcriptional activator, there is growing evidence that the p53 tumor suppressor protein is also a sequence-specific transcriptional repressor. The concept that a transcription factor can exist as both an activator and a repressor of transcription is not new. In fact, it is the rare transcription factor that can perform only one...
The p53 tumor suppressor is a tetrameric transcription factor that is posttranslational modified at <20 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity...
The p53 tumor suppressor protein plays a central role in maintaining genomic integrity. It does so by occupying a nodal point in the DNA damage control pathway. When cells are subjected to ionizing radiation or other mutagenic events, p53 mediates cell cycle arrest, senescence or programmed cell death (apoptosis). Furthermore, some evidence suggests that p53 plays a role in the recognition and repair...
MDM2 possesses three activities that, together, effectively inhibit the p53 tumor suppressor. First, it binds to p53 and sterically blocks p53 interaction with TATA box protein accessory factors thereby shutting down its transcriptional transactivation function. Second, MDM2 shuttles p53 from its site of action within the nucleus into the cytoplasm. Third, MDM2 is an E3 ligase that transfers ubiquitin...
Almost two decades subsequent to the discovery of p53, two homologues p63 and p73 were revealed. Much excitement erupted in the p53 field due to the fact that these genes bear significant homology to p53 primarily in the DNA binding domain. Although the structure of these genes is quite complex, p63 and p73 have been shown to have similar functions to p53 transcriptionally activating a number of known...
Single mutations in the DNA binding domain of p53 cause a radical shift in function from tumor suppressor to oncogene. The mutated proteins lose the negative feedback regulation mediated by MDM2. Their oncogenic activity consists of a dominant negative inhibition of the remaining wild-type p53 protein, and a gain of function (GOF) activity independent of wild-type p53 inhibition. An understanding...
p53 plays a dual role in cancer treatment being, on one hand, a major cancer preventive factor, which can kill or sensitize tumors to radio- and chemotherapy and, on the other hand, a determinant of cancer treatment side effects by inducing apoptosis in normal tissues during cancer therapy. This dualism defines two major therapeutic applications targeting p53: p53 activation to reduce viability of...
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