Multifactorial analysis ofp53 alteration in human cancer: A review (original) (raw)
Related papers
Identification of p53 and Its Isoforms in Human Breast Carcinoma Cells
The Scientific World Journal, 2014
In breast carcinoma, disruption of the p53 pathway is one of the most common genetic alterations. The observation that the p53 can express multiple protein isoforms adds a novel level of complexity to the outcome of p53 mutations. p53 expression was analysed by Western immunoblotting and immunohistochemistry using monoclonal antibodies DO-7, Pab240, and polyclonal antiserum CM-1. The more frequently p53-positive nuclear staining has been found in the invasive breast tumors. One of the most intriguing findings is that mutant p53 appears as discrete dot-shaped regions within the nucleus of breast cancer cells. In many malignant cells, the nucleolar sequestration of p53 is evident. These observations support the view that the nucleolus is involved directly in the mediation of p53 function or indirectly by the control of the localization of p53 interplayers. p53 expressed in the nuclear fraction of breast cancer cells revealed a wide spectrum of isoforms. p53 isoforms ΔNp53 (47 kDa) and Δ133p53 (35 kDa), known as dominantnegative repressors of p53 function, were detected as the most predominant variants in nuclei of invasive breast carcinoma cells. The isoforms expressed also varied between individual tumors, indicating potential roles of these p53 variants in human breast cancer.
Distinct pattern of p53 phosphorylation in human tumors
Oncogene, 2001
The protein product of the tumor suppressor gene p53 is phosphorylated on multiple residues by several protein kinases. Using a battery of 10 antibodies developed against dierent phosphorylated and acetylated residues of p53, we compared the pattern of p53 phosphorylation and acetylation in tumor-derived cell lines, tumor samples, and non-neoplastic cells. Irrespective of tumor types or the presence of p53 mutation, phosphorylation and acetylation of p53 was substantially higher in samples obtained from tumor tissues than those found in non-transformed samples. Among the 10 sites analysed, phosphorylation of residues 15, 81, 392, and acetylation were among the more frequent modi®cations. Analysis of two of the more abundant phosphorylation or acetylation sites on p53 is sucient to detect 72% of tumor-derived p53 proteins. The distinct pattern of p53 phosphorylation and acetylation in human tumors may oer a new means to monitor the status and activity of p53 in the course of tumor development and progression. Oncogene (2001) 20, 3341 ± 3347.
Mutations in p53 as potential molecular markers for human breast cancer
Proceedings of the National Academy of Sciences, 1991
Based on the high incidence of loss of heterozygosity for loci on chromosome 17p in the vicinity of the p53 locus in human breast tumors, we investigated the frequency and effects of mutations in the p53 tumor suppressor gene in mammary neoplasia. We examined the p53 gene in 20 breast cancer cell lines and 59 primary breast tumors. Northern blot analysis, immunoprecipitation, and nucleotide sequencing analysis revealed aberrant mRNA expression, over-expression of protein, and point mutations in the p53 gene in 50% of the cell lines tested. A multiplex PCR assay was developed to search for deletions in the p53 genomic locus. Multiplex PCR of genomic DNA showed that up to 36% of primary tumors contained aberrations in the p53 locus. Mutations in exons 5-9 of the p53 gene were found in 10 out of 59 (17%) of the primary tumors studies by single-stranded conformation polymorphism analysis. We conclude that, compared to amplification of HER2/NEU, MYC, or INT2 oncogene loci, p53 gene mutat...
p53 alterations in human cancer: more questions than answers
Oncogene, 2007
The strongest and undisputed fact about p53 is the high frequency of p53 alterations in human cancer and that mutant p53 proteins constitute a complex family of several hundred proteins with heterogeneous properties. Beyond these observations, the p53 pathway and its regulation in a normal cell is like a desert trail, always moving with the wind of novel findings. The field is full of black boxes that are often ignored for sake of simplicity or because they do not fit with the current dominant view. Mutant p53 protein accumulation in tumours is the best example of a preconceived idea, as there is no experimental evidence to explain this observation. In this review, we will discuss several questions concerning the activity or selection of p53 mutations. The central domain of the p53 protein targeted by 80% of p53 mutations is associated with the DNA-binding activity of the p53 protein, but it is also the binding site for several proteins that play a key role in p53 regulation such as ASPP proteins or BclxL. The role of impaired DNA binding and/or protein interactions in tumour development has not been fully elucidated. Similarly, novel animal models carrying either missense p53 mutations or inducible p53 have provided abundant observations, some of which could challenge our view on p53 function as a tumour suppressor gene. Finally, the possible clinical applications of p53 will be discussed.
The EMBO Journal
In an effort to correlate the biological activity of the p53 protein with its conformation, we analysed 14 p53 mutants representative of the most frequently observed protein alterations in human cancers, at codons 175, 248 and 273 (22% of all mutations thus far reported), all three of which contained a CpG dinucleotide. Strikingly, most of the mutants at codons 248 and 273 did not display any change in their conformation, as probed by monoclonal antibodies PAb240 and PAb1620 or by binding to hsp70 protein. For all 14 mutants tested, we found a strict correlation between the transactivation properties of p53, tested either on RGC sequences or using the WAF-1 promoter, and inhibition of cell proliferation. All these mutants showed nuclear localization. Several mutants, present at a low incidence in human tumours, displayed wild-type activity in all our assays, suggesting that the presence of a mutation is not strictly correlated with p53 protein inactivation in tumours. Further analys...
Analysis of p53 Gene Alterations in Cancer: A Critical View
25 Years of p53 Research, 2007
He threw himself into the water and swam out in search of the swans, who caught sight of him and hurried towards him, their feathers ruffled. "Kill me" cried the poor animal, hanging his head towards the surface of the water, awaiting death. But what did he see in the transparent water? He saw his own image beneath him, no longer that of an ugly, dirty grey duckling, but that of a majestic swan. There's no harm in being born in a farmyard when you hatch from a swan's egg.
Experimental and therapeutic medicine, 2010
The aim of this study was to compare the sensitivity of the serological level of anti-p53 antibodies in breast cancer patients and to correlate its expression level with patient age, histological stage and grade of tumor differentiation. Total p53 protein expression (mutant and wild-type) was also determined in the breast cancer tissues using immunohistochemistry (IHC). The serological levels of mutant p53 expression were found to be age-dependent, reaching the highest level at 50 years of age. Faint or low detection was observed in patients ≤30 years of age. Anti-p53-antibodies were detected in patients ≤40 and ≥61 years of age. The serological levels of mutant p53 protein were highly detected in all stages of breast cancer, including the early stages. However, anti-p53 antibodies reached a high level of detection only in stage III breast carcinomas. No expression was found in patients with benign breast disease. The detection of p53 mutations was dependent on the grade of tumor di...
Studying The Expression of Human P53 Gene in Patients Carrying Breast Cancer
Mustansiriyah Journal of Science, 2017
The gene P53 can activate DNA repair proteins when DNA has sustained damage. So, it is an important factor in aging. Also, P53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. For this importance, we collected thirty samples from Yarmouk hospital in Baghdad, Iraq. Twenty-nine from women patients carrying breast cancer and the last one was from healthy woman, and the samples that we have taken were embedded in paraffin wax. The extracted RNA from each sample was used to check the expression of a suppressor gene (P53) via Real time PCR. We designed primers of P53 gene on encoded sequence (Exon), to make sure generation a specific PCR product of P53 gene by converting mRNA to cDNA then PCR Product. The expression of each sample was fluctuated between 0.1 fold to 0.2 fold compared with the control (the healthy sample). The highest expression showed was samples 7 (0.2 fold), and the lowest expression showed was samples 27 (0.1 fold) that compared with control expression (sample 19). While the control expression was the highest (0.25 fold) among all samples. The results indicate that tumor may affects on a suppressor gene (P53) and can decrease the gene expression, and eventually can decrease the P53 suppressor protein that can be used it in the cell protection against cancer.
Gene Regulation by p53 in Human Cancer System
Asian Pacific Journal of Cancer Biology
TP53 proto-oncogene constitutes tumor induction in more than 50% of human cancers as it is mutated frequently in a wide range of cell lines. The transcription of TP53 is postulated to be autoregulated via either binding with TBP and CBF or via direct interaction of p53 protein with TP53 promoter, though further investigation is needed to acknowledge it. Alteration in pathways, regulated through wild type, by mutant p53 (Mutp53) give rise to immortality through interaction with other transcription factors or inducing receptor tyrosine kinases and other signal components. The missense mutation is more frequent constituting more than 60% among all mainly because of the high rate of G>A or C>T transitions in TP53, giving rise to mutation hotspots in R248, R273, etc. In addition to the loss of function, mutations in the TP53 gene also confers oncogenic functions that are not found in wild type p53, referred to as Gain of Function (GOF). GOF mutp53 has been found to promote metastas...