UMD TP53

TP53

TP53 and cancer

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MUTP53LOAD

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TP53 TUMOR SUPPRESSOR GENE

P53 FUNCTION

The tumor suppressor gene p53 is situated at the crossroads of a network of signalling pathways that are essential for cell growth regulation and apoptosis induced by genotoxic and non-genotoxic stresses (Melino et al., 2002; Vogelstein et al., 2000; Vousden & Lu, 2002). In normal unstressed cells, these upstream pathways predominantly include the binding by proteins such as MDM2, JNK or Pirh2 that promote p53 degradation via the ubiquitin/proteasome pathway (figure below).

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After genotoxic or non-genotoxic stresses, these pathways include signalling mainly performed by kinases and acetylases that regulate p53 stability and conformation leading to activation of p53 transcriptional activity. A plethora of proteins have been found to bind various regions of p53 in order to regulate the specificity of its activity. Downstream signalling includes a large series of genes that are activated by the transactivating properties of p53. This occurs via specific DNA binding of the p53 protein to a p53 response element (p53 RE) that is found either in the promoter or in the intron of target genes. Regardless of the type of stress, the final outcome of p53 activation is either cell cycle arrest and DNA repair or apoptosis, but the mechanism leading to the choice between these two fates has not yet been elucidated. Numerous studies have analysed the pattern of genes induced after p53 activation using global technologies such as SAGE, DNA array, Suppression Subtractive Hybridisation (SSH) or by cloning functional p53-binding sites. These studies emphasize the heterogeneity of the p53 response that is highly variable depending on the cell type, the nature and amount of DNA damage, the genetic background of the cells and the amount of p53 protein. Several criteria have been described to define a bona fide p53 response gene: i) the existence of p53 RE specifically recognized by p53; ii) the ability of these sites to act as a p53 RE activating transcription in a wild type p53 dependent manner; iii) the response of the element to p53 in the context of the endogenous promoter and iv) induction of the target gene after cellular stress such as DNA damage in cells containing wild type, but not a mutant form of p53. These criteria have recently been challenged, as several p53-induced genes lack p53RE. It has also been shown that, in the PIG3 gene, p53 DNA binding does not need the canonical response element, but binds efficiently to a polymorphic microsatellite sequence localized in the promoter. Furthermore, several cellular genes lacking a p53 RE have been shown to be downregulated by wild type p53.

P53 GENE

The human tumor suppressor gene p53 is localized on the short arm of chromosome 17(17p13). Several p53 genes have been cloned in their entirety in various species. Their organization is highly similar and they share the following characteristics: i) The presence of a very large intron (10, 6.1, 6.2, 6.5, 7.7 kb for man, mouse, rat, hamster and xenopus respectively ) at the 5' end of the gene. For mammalian p53, this intron is located between exons 1 and 2, while in xenopus, it is found between exons 2 and 3. Its biological significance is totally unknown at the present time. ii) Exon 1 is always non-coding. It has been demonstrated that this region could form a stable stem-loop structure which binds tightly to wild type p53 but not to mutant p53. This binding inhibits specifically p53 mRNA translation and could provide a means for the control of p53 protein level in the cell. iii) The intron/exon distribution between these five genes is globally similar. The introns vary in size but divide up the gene in a very similar manner, with the exception of intron 6 whose counterpart is absent in the rat, and intron 3 in xenopus which divides up exons 3 and 4 differently. A pseudogene has been characterized and sequenced in the mouse and corresponds to a copy of mRNA that has been integrated in the cellular genome after reverse transcription. Two similar pseudogenes have also been identified in the rat.


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P53 PROTEIN

Human p53 protein (Hp53) can be divided into five domains, each corresponding to specific functions.
I) The amino-terminus part 1-39 contains the acidic transactivation domain and the mdm2 protein binding site.
II) Region 40-100 contains series repeated proline residues that are conserved in the majority of p53.
III) The central region (101-306) contains the DNA binding domain. It is the target of 90% of p53 mutations found in human cancers.
IV) The oligomerization domain (307-355) consists of a beta-strand, followed by an alpha-helix necessary for dimerization, as p53 is composed of a dimer of two dimers. A nuclear export signal is localized in this oligomerization domain.
V) The carboxy-terminus of p53 (356-393) contains 3 nuclear localization signals and a non-specific DNA binding domain that binds to damaged DNA. This region is also involved in downregulation of DNA binding of the central domain.


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USEFUL LINKS

The TP53 web site
TP53 GENECARDS
TP53 OMIM
TP53 at Atlas of Genetics and Cytogenetics in Oncology and Haematology
TP53 gene at Entre
TP53 at unigene
TP53 protein sequence at NCBI GDB
TP53 mRNA at NCBI
TP53 Gene at NCBI