Loss of Function of TP53 in Cancer

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R-HSA-9723907
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Pathway
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Homo sapiens
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TP53 is the most frequently mutated tumor suppressor gene, with mutations present in more than 50% of human tumors and germline mutation in TP53 being underlying cause of the cancer-predisposing Li-Fraumeni syndrome (reviewed in Monti et al. 2020). The TP53 gene maps to chromosomal band 17p13 and encodes a transcription factor that contains four functional domains. A transactivation domain (TAD) involves amino acid residues 1-61 and is involved in interaction with components of the transcription machinery. A DNA binding domain (DBD) involves amino acid residues 94-290 and interacts with specific DNA target sequences called p53 response elements. A C-terminal domain (CTD) involves residues 357-393 and regulates DNA binding (reviewed in Monti et al. 2020). A tetramerization domain (TD) involves amino acids 325-355 and is needed for the formation of TP53 homotetramers. TP53 is considered the “guardian of the genome” (Lane 1992) as it is activated by DNA damage to initiate, depending on the amount of damage, cell cycle arrest, senescence or apoptosis (reviewed in Reinhardt and Schumacher 2012). In addition, TP53 regulates the expression of DNA repair genes, and is involved in the regulation of metabolism and autophagy (reviewed in Monti et al. 2020).
Most cancer-derived TP53 mutations are missense mutations that affect the central DNA binding domain of TP53 (amino acid residues 94-312). Eight hotspot amino acid substitutions in this region (R175H, G245S, R248Q, R248W, R249S, R273H, R273S and R282W) are found in close to 30% of TP53-mutated cancers. Based on their functional impact, TP53 mutations can be classified as 1) loss-of-function (LOF), 2) partial LOF (which may involve temperature sensitivity); 3) wild type-like (WT-L) or super-transactivating (ST) mutants; 4) mutants with altered specificity (AS), which are active or partially active on some but inactive on other TP53 target genes; 5) dominant-negative (DN) mutants, able to tetramerize with and inhibit the activity of the wild type TP53 protein. Some of the TP53 mutants, especially in the category of ST and AS mutants, are gain-of-function (GOF) mutants, able to interact with novel target genes and/or novel components of the transcriptional machinery (reviewed in Monti et al. 2020, and Gencel-Augusto and Lozano 2020).
Due to the complex function of WT-L, ST, AS and DN mutants of TP53, we have so far focused on annotating LOF mutants of TP53 which are unable to oligomerize due to mutations in the TD. Although accounting for a small percent of TP53 mutants, TD mutant are therefore considered to be completely defective in transcriptional activity, with no possibility of AS, DN and GOF effects (Chène and Bechter 1999, reviewed in Chène 2001, and Kamada et al. 2016). However, when overexpressed, some missense TD mutants of TP53 can form homotetramers and heterotetramers with the wild type TP53 which are partially functional and some extent of AS, DN and GOF effects may not be excluded for those mutants (Atz et al. 2000, reviewed in Chène 2001). In addition, the synthetic mutant p153(1-320) which consists of the first 320 amino acids and lacks the TD and CTD, while unable to tetramerize, can form stacked oligomers at the recombinant target gene promoter and induce transcription at a low level. Stacked oligomers are formed through interactions that involve amino acid residues outside the TD, which are facilitated by the presence of a target DNA sequence (Stenger et al. 1994).

Literature References
PubMed ID Title Journal Year
26572807 Tetramer formation of tumor suppressor protein p53: Structure, function, and applications

Kamada, R, Imagawa, T, Nomura, T, Toguchi, Y, Sakaguchi, K

Biopolymers 2016
22265392 The p53 network: cellular and systemic DNA damage responses in aging and cancer

Schumacher, B, Reinhardt, HC

Trends Genet 2012
7813439 p53 oligomerization and DNA looping are linked with transcriptional activation

Mastrangelo, IA, Reed, M, Stenger, JE, Hough, PV, Wang, P, Tegtmeyer, P, Mayr, GA, Wang, Y

EMBO J. 1994
1614522 Cancer. p53, guardian of the genome

Lane, DP

Nature 1992
11420672 The role of tetramerization in p53 function

Chène, P

Oncogene 2001
32873579 p53 tetramerization: at the center of the dominant-negative effect of mutant p53

Lozano, G, Gencel-Augusto, J

Genes Dev 2020
10653977 Function, oligomerization, and conformation of tumor-associated p53 proteins with mutated C-terminus

Atz, J, Wagner, P, Roemer, K

J Cell Biochem 2000
10064694 p53 mutants without a functional tetramerisation domain are not oncogenic

Bechter, E, Chène, P

J Mol Biol 1999
33194757 Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

Bomben, R, Gattei, V, Speciale, A, Monti, P, Gentile, M, Fronza, G, Morabito, F, Fais, F, Taiana, E, Ferrarini, M, Menichini, P, Cutrona, G, Neri, A

Front Oncol 2020
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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