Tumor Protein p53

Alternative Names

  • TP53
  • P53
  • Transformation-Related Protein 53
  • TRP53

Associated Diseases

Breast Cancer
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OMIM Number

191170

NCBI Gene ID

7157

Uniprot ID

P04637

Length

25,772 bases

No. of Exons

12

No. of isoforms

9

Protein Name

Cellular tumor antigen p53

Molecular Mass

43,653 Da

Amino Acid Count

393

Genomic Location

chr17:7,661,779-7,687,550

Gene Map Locus
17p13.1

Description

Tumor Protein 53 (p53) is a transcription factor that is known to function as a tumor suppressor. p53 controls the cell cycle, by arresting growth either before DNA replication in the G1 phase or before mitosis in the G2 phase of the cell cycle. It has recently been shown that the p53 signal transduction network is actually inactive or poorly active in normal cells. Ubiquitination and subsequent degradation of the transcribed p53 also keeps its level in check in normal cells. However, the gene is activated by stress signals, such as carcinogen-induced DNA damage, abnormal proliferative signals, hypoxia, or loss of cell adhesion. In addition, under the influence of such stress signals, the ubiquitin dependent degeneration of the protein is also affected, resulting in a high concentration of the protein within the cell.

The p53 protein binds to promoters of a number of specific genes as a transcription factor, and thereby, initiates their transcription. Most of the genes transcribed fall under one of the following categories: genes involved in controlling the cell cycle (p21 WAF1/CIP1, WIP1, EGFR, and other Cyclins), genes involved in DNA repair (GADD45, PCNA), genes involved in angiogenesis (TSP-1, BAI1), and genes involved in cellular stress response (TP53TG1, CSR, PIG3). Through the transcription of these proteins, p53 is able to play an important role in the processes of prevention of tumor development, inhibition of abnormal growth of cells, DNA repair, and inhibition of angiogenesis.

The role of the p53 protein in tumor suppression is clearly demonstrated by mutations in the gene. Mutations in one copy of the gene may lead to a disease known as Li-Fraumeni Syndrome, characterized by a propensity to develop tumors in early adulthood. Interestingly, more than 50% of human tumors have been found to contain a mutation or deletion in the p53 gene.

Epidemiology in the Arab World

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Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_000546.6:c.215C>G Lebanonchr17:7676154Benign, Drug ResponseUncertain SignificanceBreast CancerNG_017013.2:g.16397C>G; NM_000546.6:c.215C>G ; NP_000537.3:p.Pro72Arg104252212351
NM_000546.6:c.245C>TLebanonchr17:7676124Benign, Likely BenignPathogenicBreast CancerNG_017013.2:g.16427C>T; NM_000546.6:c.245C>T; NP_000537.3:p.Pro82Leu534447939182946
NM_000546.6:c.469G>A Lebanonchr17:7675143Uncertain SignificanceBreast CancerNG_017013.2:g.17408G>A; NM_000546.6:c.469G>A ; NP_000537.3:p.Val157Ile121912654185404
NM_000546.6:c.673-36G>CLebanonchr17:7674326BenignAssociationBreast CancerNG_017013.2:g.18225G>C; NM_000546.6:c.673-36G>C 17880604221184

Other Reports

Arab

Al-Shamsi et al. 2021 delineated the somatic mutational spectrum and frequency in Arab women with breast cancer. 78 women mostly with stage 3 or 4 breast cancer exhibited mutations and mutation rates in the following genes: TP53, 23.1%; ATM, 2.6%; IDH1, 2.6%; IDH2, 3.8%; PTEN, 7.7%; PIK3CA, 15.4%; APC, 7.7%; NPM1, 2.5%; MPL, 1.3%; JAK2, 2.5%; KIT, 7.7%; KRAS, 3.8%; and NRAS, 3.8%

Kuwait

Temmim et al. (2001) carried out an immunohistochemical analysis of p53 on 82 young Kuwaiti women with breast cancer with an age of < or = 30 years old. The analysis was done in association with histopathological grade, lymph node status, estrogen (ER) and progesterone receptor (PgR) content, tumor cell proliferation (immunostaining for Ki-67) and expression of c-erbB-2 oncoprotein. Results demonstrated p53 immunostaining in 57% of the carcinomas, of those 65% revealed positive immunostaining for c-erbB-2. 64% of tumors with p53 overexpression were found to be aneuploid, while 65% of the p53 positive tumors were node positive. ER-negative tumors were found in 94%of the p53 immunopositive carcinomas, whereas PgR was not found in 96% of this subclass of patients. Grade III p53 positive carcinomas were the most common comprising 77%, whereas grades I and II covered 2% and 21%, respectively, without demonstrating any relation among tumor grade or size and p53 expression. A negative significant association was detected among ER- and PgR-content (p = 0.006) and immunostaining for p53. Temmim et al. (2001) demonstrated that the correlation of negative hormone receptor status and positivity for p53 immunostaining indicates greater tumor aggressiveness.

Alkhalaf et al. (2007) conducted the first pilot study on Kuwaitis suffering from coronary artery disease (CAD) and diabetes, aiming at investigating the possible association between the polymorphism in the p53 gene at codon 72 and the development of CAD and diabetes. Alkhalaf et al. (2006) analyzed 158 patients with CAD and 110 matching controls. In addition, 142 patients with diabetes and 130 matching controls were also analyzed in this study. The polymorphism at codon 72 of the p53 gene was determined by using two sets of primers, one to amplify the Arg allele and the other to amplify the Pro allele. Analysis of CAD patients revealed an alarming significant association between the disease and the existence of diabetes (P=0.0007). Also, CAD patients had significantly higher level of triglyceride (P<0.0001) and cholesterol (P<0.0001) as compared to control. Based on these results, Alkhalaf et al. (2006) concluded that CAD seems to be strongly linked to diabetes in Kuwait. As for the polymorphism in p53 gene codon 72, Alkhalaf et al. (2006) could not detect any association with the genotype Pro/Pro, Pro/Arg or Arg/Arg distribution (P=0.28) or allele (Pro or Arg) frequency (P=0.25) in CAD patients. Similarly, no association was found with the genotype Pro/Pro, Pro/Arg or Arg/Arg distribution (P=0.44) or allele (Pro or Arg) frequency (P=0.26) in the diabetic patients. These results did not reveal a significant association between the development of CAD or diabetes in Kuwait and polymorphism in the p53 gene at codon 72, which confirms other similar results obtained in the USA and Asia. Despite that, Alkhalaf et al. (2006) suggested that the results in this study can be used as baseline for future studies in which a larger sample size is obtained and in which the ethnic background is known since it may influence the outcome of the results. They also suggested that other reported polymorphisms at the p53 gene locus should also be investigated before making any final conclusions regarding the association of p53 polymorphisms and CAD.

Oman

Al-Moundhri et al. (2003) were the first to investigate the prognostic roles of the proto-oncogenes, p53, Bcl-2, and HER-2/neu, in the course of breast cancer in Arab females in Oman. A total of 72 women (mean age: 49 years) with breast cancer were utilized for the study, and immuno-histochemical staining was used to study p53 antigen expression. Positivity of the p53 protein was considered if more than 10% of the tumor cells showed nuclear staining. Overexpression of p53 was detected in 41.7% of the patients, and it was found to significantly correlate with the lack of ER (Estrogen Receptor) and PR (Progesterone Receptor) expression, poor tumor differentiation, and inversely correlated with Bcl-2 expression but no such relationship was seen with tumor size, lymph node involvement or HER-1/neu expression and was mostly seen in those with ages less than 40 years and premenopausal. Expression of p53 was also found to be inversely associated with survival, as 36 months and 80.1 months were the median survival for p53 positive and negative patients, respectively. Multivariate analysis revealed that p53 overexpression, lack of Bcl-2 expression, tumor size more than 5 cm, and lymph node involvement were significant prognostic variables.

Al-Moundhri et al. (2005) determined the prognostic effect of p53 expression in Arab patients diagnosed with gastric carcinoma and studied the association of its expression with the clinico-pathological features, along with other tumor suppressor genes. The proteins expression was determined in 121 paraffin-embedded tumor blocks prepared from patients diagnosed with gastric cancer (mean age: 60.2 years) by immuno-histochemical staining with the use of monoclonal antibodies. Breast adenocarcinoma samples were used as positive controls, while the negative controls were obtained by omitting the primary antibodies before incubation. Over-expression of p53 was considered if more than 10% of the tumor cells showed nuclear staining. Over-expression of p53 was detected in 53.7% of the patients, and a strong correlation between p53, p27 kip1, and Ki67 was detected and so was a significant association between HER-2/neu and p53. Both p53 and Ki67 over-expression were seen in patients less than 60 years, but only p53 correlated with tumor size more than 5 cm. Univariate analysis revealed that fungating and infiltrative tumors, tumor size more than 5 cm, lymph node metastasis, pathological T3 and T4 disease, overall stage III and IV along with positive p53 immunoreactivity were associated with poor prognosis, while multivariate analysis showed only p53 over-expression and lymph node involvement as independent poor prognosis predictors. On combined analysis of p53 and p27 kip1 expression, best survival (28 months) was associated with tumors which exhibited p27 kip1 and not p53, while the expression of p53 alone was associated with the worst survival (13 months). Al-Moundhri et al. (2005) concluded that by measuring the p53 and p27 kip1 proteins along with lymph node status, identification of patients with poor prognosis would be possible and their treatment modalities could be optimized.

Saudi Arabia

Alshatwi et al. (2012) studied a cohort of 200 subjects to study the association between the TP53 72Arg/Pro polymorphisms and risk of breast cancer.  The study included 100 patients with breast cancer who were clinically and histopathologically diagnosed at King Khalid University Hospital from January 2009 to October 2010 and 100 healthy women of similar age (50 ± 5 years) who were voluntarily enrolled as controls.  Both study groups were from Riyadh, Saudi Arabia.  The demographic details revealed early onset and late diagnosis of breast cancer in these patients.  The presence of TP53 Pro/Pro genotype, was found not to be associated with an increased risk of breast cancer.  However, the presence of both MDM2 GG and TP53 72Pro/Pro genotypes was associated with an even higher risk for breast cancer compared with those who lacked both genotypes.  These molecular epidemiological findings were found to be consistent with the results obtained from functional analyses.

Sudan

Masri et al. (2002) studied a cohort of 20 breast cancer patients and tested them for germ line and somatic mutation in their BRCA2 exon 11 as well as the main conserved area of the p53 tumor suppressor gene. The results indicated that both regions may play a limited role in the pathogenesis of breast cancer in those patients. The fact that there are no somatic mutations detected in p53 was particularly surprising as the expected rate for mutations in breast cancer is 30-50%.

United Arab Emirates

In a retrospective study of breast cancer patients in the UAE, Altinoz et al (2020) identified an Emirati patients with pathogenic variant in the TP53 gene. An additional  EmIrati was found to have variants of uncertain significance in the same gene.  

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