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A considerable interest has been put in the identification of biased regions in proteins. These regions are frequently associated with a structural role in the cell and particularly with protein disorder. Here, we have investigated the intrinsically disordered regions (IDRs) in the human charged biased proteins identified in our earlier work. We found that 65% of charged biased proteins contained significant IDRs involved particularly in DNA and RNA binding. Also, we have observed that these proteins are well conserved in metazoans and more particularly in mammalian. In addition, the IDRs are located largely in N-terminal, C-terminal sequence flanking the functional domains (FD) and slightly less in (FD) itself. Our work also supports the association between protein disorder and protein-protein/DNA interaction. An example will be described.

Protein-protein interaction (PPI) network analysis has been considered as a useful approach to explore the mechanisms of complex diseases, such as cancer. To date, many proteins have been reported to involve in the development of cancer. Exploration of cancer proteins in the human PPI network may provide important biological information to uncover molecular mechanisms of cancer. Here, we have explored network characteristics (including degree, betweenness, clustering coefficient and shortest-path distance) of cancer proteins of the human nuclear and tyrosine kinases receptors network (NR-RTK) constructed in our earlier work. We found that the network topology of cancer proteins in this network have some specific features. Relative to the non-cancer proteins, the cancer proteins have likely higher degree, higher betweenness, similar clustering coefficient and similar shortest-path distance. Finally, we found that the cancer proteins were involved mainly in signalling pathways which dysfunction is directly related to cancer onset. These findings are helpful for cancer candidate protein prioritization and verification, and identification of key pathways involved in cancer disease.

Background: The prognosis of breast carcinoma is related to a large variety of clinical and pathological factors. Currently, only oestrogen (ER) and progesterone (PR) receptors and human epidermal growth factor receptor 2 (HER2) are used in routine pathological assessment as biomarkers. The aim of this study was to evaluate the prognostic impact of epidermal growth factor receptor (EGFR) expression individually and in combination to classical biomarkers (HER2, ER, and PR), and its relation to tumors with triple negative profile in Tunisian breast carcinoma., Methods: Immunohistochemistry was used to estimate the rate expression of these receptors. Univariate and multivariate analyses were used to explore the prognostic significance of EGFR in this study., Results: The expression rate of EGFR was 28.6%. EGFR expression was inversely correlated to that of ER (P < 0.001). Significant correlations between the expression of EGFR and the high histological Scarff-Bloom-Richardson (SBR) grade (P = 0.038) and also with tumors size (P = 0.041) were observed. The triple negative profile (TN: ER-/PR-/HER2-) was present in 17.3% of cases. EGFR overexpression was positively associated with this clinical aggressive profile (P < 0.001). Survival analysis showed that EGFR expression was associated with poor survival of patients (P = 0.004). In multivariate analysis, EGFR expression (P = 0.035) was found to be independent prognostic factors (significantly correlated to survival)., Conclusion: EGFR overexpression was observed in 28.6% of Tunisian breast carcinoma, associated with unfavorable prognosis and with triple negative tumors. Systemically evaluation of EGFR in breast carcinoma could benefit especially to TN subgroup from EGFR targeting agents.

Receptor tyrosine kinases (RTKs) are transmembrane proteins involved in the control of fundamental cellular processes in metazoans. RTKs possess a general structure that includes an extracellular domain, a transmembrane domain and a highly conserved tyrosine kinase domain. RTKs are classified according to their variable extracellular ligand-binding domain. Studies of human RTK members have yielded a wealth of information elucidating their importance. Improper functioning of these enzymes due to mutations, mainly in the kinase domain, is often manifested in various human diseases and is known to be involved in several types of cancer. Here we summarize most of human RTKs, their cognate ligands, as well as related diseases and discuss the eventual use of certain RTKs as new therapeutic targets.

Understanding the functions of single nucleotide polymorphisms (SNPs) can greatly help to understand the genetic basis of human complex diseases such as cancer. However, identifying functional SNPs among the huge number of available SNPs is challenging. In this study, we analyzed the genetic variations that can alter the expression and function of ErbB proteins using different computational tools. For noncoding SNP, we found that one SNP located in 59UTR of ErbB1 gene might change protein expression level and two SNPS located in regulatory regions might affect transcriptional regulation of Erbb1 and Erbb4. For coding SNPs we predicted that 25 nonsynonymous SNPs (most of them in ErbB1 gene) might disrupt the protein function among which 22 might alter protein structure. Prediction regarding the potential effect of the SNPs showed that 13 of them located within the tyrosine kinase or the ligand binding domain are likely to be associated with cancer.

The receptors for thyroid hormone (THR) and oestrogen (ESR) are prototypes of nuclear transcription factors that regulate the expression of target genes. Genetic alterations in the genes of these receptors were found to be involved in cancer development. In this study we investigated the association of one SNP (rs2228480, T594T) and one microsatellite marker (D6S440) within the ESR1 gene and a dinucleotide repeat (D17S2189) within the THRA gene, with thyroid cancer risk. A case-control association study was conducted with 299 healthy individuals and 106 patients with thyroid cancer. Genotypic and allelic frequencies for the dinucleotide repeat in the ESR1 gene were similar between thyroid cancer patients and controls. For the AC repeat in the THRA gene, a slightly significant difference was found for the genotype 18/20 between the two groups (P = 0.034), which suggests that alleles with less than 20 repeats might have a protective effect in thyroid cancer risk. For the SNP T594T, the A allele was much more prevalent in patients than in controls and was highly associated with the risk of thyroid cancer (OR: 4,56; IC: 3.23-6.44; P < 10(-18)) and seems to have an additive mode of action. In conclusion, our data suggest that the SNP T594T but not the D6S440 and D17S189 is associated with thyroid cancer risk.

Overexpression or dysfunction of EGFR and other ErbBs is known to be involved in many human cancers. The first intron of several genes, including ErbBs, has an important regulatory function in transcription. In intron 1 of the EGFR gene, simple CA repeats (CA-SSR) have been found to be associated with the level of transcriptional modulation of the EGFR both in vitro and in vivo. The aim of this work was to screen for conserved dinucleotide repeats located in introns of the human ErbB genes. Pairwise BLAST was used to identify paralogs to intron 1 of EGFR in the HER2 gene. Dinucleotide tandem repeats were searched in intron sequences using the Tandem Repeat Software to restrict detection of dinucleotide microsatellites containing at least 10 repeats. With multiple alignment, short conserved DNA sequences should also be detected, revealing the presence of potential regulatory elements near CA repeats. We found that the nearest homolog to intron 1 in the EGFR gene is intron 4 of the HER2 gene. The experimental validation of four predicted short tandem repeats (STRs) (three dinucleotide repeats in intron 1 of the EGFR and one in intron 4 of the HER2 gene) by genotyping of about 100 controls showed that these STRs are polymorphic. In a case-control study to test the association of the four new polymorphic STRs with breast cancer, a significant allelic association was found for all STRs (P < 0.001). These results suggest that the role of transcriptional regulation of CA repeats in intron 1 of the EGFR gene might be conserved in other ErbB genes.