Browsing by Subject "TP53"

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Open Access
Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma
(Elsevier, 2010) Acun T.; Terzioǧlu-Kara, E.; Konu, O.; Ozturk, M.; Yakicier, M. C.
Loss of function of the p53 protein, which may occur through a range of molecular events, is critical in hepatocellular carcinoma (HCC) evolution. MDM2, an oncogene, acts as a major regulator of the p53 protein. A polymorphism in the MDM2 promoter, SNP309 (T/G), has been shown to alter protein expression and may thus play a role in carcinogenesis. MDM2 SNP309 is also associated with HCC. However, the role of SNP309 in hepatocarcinogenesis with respect to TP53 mutations is unknown. In this study, we investigated the distribution of the MDM2 SNP309 genotype and somatic TP53 (the p53 tumor suppressor gene) mutations in 99 human HCC samples from Africa, Europe, China and Japan. Samples exhibited striking geographical differences in their distribution of SNP309 genotypes. The frequency and spectrum of p53 mutations also varied geographically; TP53 mutations were frequent in Africa, where the SNP309 T/T genotype predominated but were rare in Europe and Japan, where the SNP309 G allele was present more frequently. TP53 mutations were detected in 18% (4/22) of SNP309 T/G and G/G and 82% (18/22) of SNP309 T/T genotype holders; this difference was statistically highly significant (P-value = 0.0006). Our results indicated that the presence of the SNP309 G allele is inversely associated with the presence of somatic TP53 mutations because they only coincided in 4% of HCC cases. This finding suggests that the SNP309 G allele may functionally replace p53 mutations, and in addition to known etiological factors, may be partly responsible for differential HCC prevalence. © 2009 Elsevier B.V. All rights reserved.
Open Access
SOX2 in focus: association of SOX2 copy number variation with TP53 mutation in TCGA pancancer cohorts and codon optimized design for de novo SOX2 synthesis using novel shiny application
(2024-01) Çelik, Siber Güneş
Recombinant proteins are crucial for diverse research applications such as biosensors and cancer studies. Proteins are engineered through de novo gene synthesis methods. Numerous tools and databases have emerged to facilitate the design of recombinant proteins, starting from the design of the gene sequence. De novo DNA synthesis enables the synthesis of custom-designed sequences, allowing codon optimization to enhance expression yield in heterologous systems. In cancer research, recombinant expression of proteins involved in tumorigenesis-related signaling pathways is employed for functional studies, potentially revealing new therapeutic targets. A notable example is the pivotal role of SOX2 expression in the formation of cancer stem cells (CSCs) across various cancer types. Previous studies highlight SOX2 expression functionally overlaps with TP53 expression on the PI3K/AKT signaling pathway. This association may stem from the p53-MDM2 interaction. This thesis investigates the association between SOX2 copy number gain and TP53 mutations within TCGA PanCancer cohorts. Fisher’s exact test results reveal varying association, dependent on tissue type and specific driver mutations within each cancer type. The findings suggest the potential therapeutic relevance of SOX2 in cancer research. Furthermore, the thesis employs an in-silico approach to design de novo SOX2 synthesis, utilizing a novel shiny app that integrates codon optimization and primer design functionalities. The app enables simultaneous codon optimization for multiple expression systems and offers distance analysis through hierarchical clustering. Codon optimization feature provides control over the rate of replacement value for codon substitution which validated through a case study involving human insulin. Finally, app design set of overlapping primers with synchronized melting temperature to be used in PCR assembly for de novo SOX2 gene synthesis.
Open Access
TP53 mutations in familial breast cancer: Functional aspects
(John Wiley & Sons, Inc., 2003) Gasco, M.; Yulug, I. G.; Crook, T.
Mutation in p53 (TP53) remains one of the most commonly described genetic events in human neoplasia. The occurrence of mutations is somewhat less common in sporadic breast carcinomas than in other cancers, with an overall frequency of about 20%. There is, however, evidence that p53 is mutated at a significantly higher frequency in breast carcinomas arising in carriers of germ-line BRCA1 and BRCA2 mutations. Some of the p53 mutants identified in BRCA1 and BRCA2 mutation carriers are either previously undescribed or infrequently reported in sporadic human cancers. Functional characterization of such mutants in various systems has revealed that they frequently possess properties not commonly associated with those occurring in sporadic cases: they retain apoptosis-inducing, transactivating, and growth-inhibitory activities similar to the wild-type protein, yet are compromised for transformation suppression and also possess an independent transforming phenotype. The occurrence of such mutants in familial breast cancer implies the operation of distinct selective pressures during tumorigenesis in BRCA-associated breast cancers.