TP53 Gene

The TP53 gene (TP53 is the acronym for Tumor Protein 53) is a tumor suppressor gene. In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene comprises 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. TP53 orthologs have been identified in most mammals for which complete genome data are now available.

The gene encodes the tumour suppressor protein p53, which contains transcription activation, DNA binding and oligomerization domains. The transcription factor Tp53 acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on physiological circumstances and cell type (Guo A et al. 2000;Louria-Hayon I et al. 2003). P53 responds to various cellular stress factors to regulate the expression of target genes and thereby induce cell cycle arrest, apoptosis, senescence, DNA repair or metabolic changes.

TP53 mutations occur in all types of cancer. Loss of a tumor suppressor usually occurs through major deleterious events such as frameshift mutations or premature stop codons. However, in TP53, many of the mutations observed in cancer are single nucleotide missense variants. For example, UV-induced genomic signatures (C>t or CC>TT) are detected in atypical fibroxanthoma and pleomorphic dermal sarcoma. They are regarded as the main risk factors for the development of these tumors.

Mutations associated with myelodysplastic syndrome have also been described. These are also seen as a rather unfavorable prognostic sign. An important paralog of this gene is TP73.

Alternative splicing of the TP53 gene (see mutations below) and the use of alternative promoters lead to several transcript variants and isoforms. Tp53 mutations are found in all malignant tumor types. They contribute to the complex network of molecular events that lead to tumor formation. Loss of a tumor suppressor usually occurs through major deleterious events, such as frameshift mutations or premature stop codons. There is no single hotspot in the DNA binding domain, but the majority of mutations occur at amino acid positions 175, 245, 248, 273 and 282.

In order for the encoded protein to fulfill its biological function, four p53 polypeptides must form a tetramer that acts as a transcription factor. Therefore, even an inactivating mutation in one of the four polypeptides can lead to a dominant-negative phenotype of varying degrees.

Germline-associated TP53 mutations are the hallmark of Li-Fraumeni syndrome, an autosomal dominant inherited tumor predisposition syndrome in which children and adolescents develop multiple tumors, particularly of the adrenal gland, soft tissue, bone and mammary gland. It was also found that many variants (both germline and somatic) have a prognostic influence on the outcome of patients.

1. An W et al. (2004) Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117:735-748
2. Barbosa K et al.(2019) The role of TP53 in acute myeloid leukemia: Challenges and opportunities. Genes Chromosomes Cancer 58:875-888.
3. Bergamaschi D et al. (2003) iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet 33:162-7.
4. Guo A et al. (2000) The function of PML in p53-dependent apoptosis. Nat Cell Biol 10:730-736.
5. Huarte M et al. (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142:409-419.
6. Jiao XD et al. (2018) The prognostic value of TP53 and its correlation with EGFR mutation in advanced non-small cell lung cancer, an analysis based on cBioPortal data base. Lung Cancer123:70-75.
7. Louria-Hayon I et al. (2003) The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 278:33134-33141.
8. Nieuwenburg SA et al. (2020) Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome. Fam Cancer 19:347-351.
9. Petry V et al. (2020) Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome). Fam Cancer 19:47-53.
10. Valdez JM et al. (2017) Li-Fraumeni syndrome: aparadigm for the understanding of hereditary cancer predisposition. Br JHaematol 176:539-552.