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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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background : The Angiotensin-Converting Enzyme (ACE) is a candidate gene in the aetiology of several common diseases. The study of the haplotype structure of this gene is of interest in diagnosis and in pharmacogenomics. Aim : The study investigated the haplotype profile of single nucleotide polymorphisms (SNPs) within the ACE gene in the Tunisian population and compared it with other populations. Subjects and methods : Five SNPs (rs1800764, rs4291, rs4309, rs4331, rs4340) covering a region of 15.6&ThickSpace;kb of the ACE gene were typed by PCR-digestion in a sample of 100 healthy subjects. Results : All SNPs were polymorphic and in Hardy–Weinberg equilibrium. A total of 21 haplotypes were identified but only eight had a frequency of more than 1%. The four most common haplotypes had a cumulative frequency of 87.4%. The ‘Yin–Yang’ phenomenon (the two major haplotypes are complementary at all sites) was found. Linkage disequilibrium between all pairs of loci was highly significant ( p -5 ). A simple and efficient statistical procedure was used to identify three important SNPs. Conclusion : The Tunisian population showed a different haplotype structure from the European one for the ACE gene and three important SNPs were identified. These will be very helpful in future association studies in the Tunisian and North African populations. Résumé. Arrière plan: Le gène de l’enzyme de conversion de l’angiotensine (ECA) peut être potentiellement impliqué dans l’étiologie de plusieurs maladies courantes. L’étude de la structure de son haplotype est donc utile pour la diagnose comme pour les recherches pharmacogénomiques. Objectif: Etudier le profile haplotypique des polymorphismes de nucléotides uniques (PNU) dans le gène ECA de la population tunisienne et le comparer à d’autres populations. Trois PNU importants pour leur emploi dans les futures études d’association ont été identifiés. Sujets et méthodes: Cinq PNU (rs1800764, rs4291, rs4309, rs4331, rs4340) couvrant une région de 15,6 kb du gène ECA ont été typés par PCR-RFLP dans un échantillon de 100 personnes en bonne santé. Résultats: Tous les PNU étaient polymorphiques et en équilibre de Hardy-Weinberg. Un total de 21 haplotypes ont été identifiés, mais seulement huit avaient une fréquence supérieure à 1%. Les quatre haplotypes les plus communs avaient une fréquence cumulée de 87,4%. On a rencontré le phénomène “Yin-Yang ” (les deux haplotypes majeurs sont complémentaires à tous les sites). Le déséquilibre de linkage entre toutes les paires de loci était hautement significatif ( p &ThickSpace; –5 ). Une méthode statistique simple et efficace a été utilisée pour identifier trois PNU importants. Conclusion: La population tunisienne présente une structure haplotypique différente de celle des européens pour le gène ECA et trois PNU importants ont été identifiés. Ils seront très utiles pour les futures études d’association dans les populations tunisienne et nord-africaines. Zusammenfassung. Hintergrund: Das Angiotensin-Converting Enzym (ACE) ist ein Kandidatengen in der Ätiologie verschiedener häufiger Krankheiten. Die Untersuchung der Haplotypstruktur dieses Gens ist bei der Diagnostik und der Pharmakogenomik von Interesse. Ziel: Die Studie untersuchte das Haplotypprofil von Einzelnukleotidpolymorphismen (single nucleotide polymorphisms, SNPs) innerhalb des ACE-Gens in der Tunesischen Bevölkerung und verglich es mit anderen Populationen. Drei für den späteren Gebrauch in Assoziationsstudien bedeutsame SNPs wurden identifiziert. Probanden und Methoden: Fünf SNPs (rs1800764, rs4291, rs4309, rs4331, rs4340), die sich über eine Region von 15,6&ThickSpace;kb des ACE-Gens erstrecken, wurden mit PCR-RFLP in einer Stichprobe von 100 gesunden Probanden typisiert. Ergebnisse: Alle SNPs waren polymorph und im Hardy–Weinberg Gleichgewicht. Insgesamt 21 Haplotypen wurden identifiziert, aber nur acht traten in einer Häufigkeit von über 1% auf. Die vier häufigsten Haplotypen hatten eine kumulative Häufigkeit von 87,4%. Das ‘Yin–Yang’-Phänomen wurde gefunden (die beiden wichtigsten Haplotypen sind allseits komplementär). Das Kopplungsungleichgewicht zwischen den jeweils gepaarten Loci war hochsignifikant ( p &ThickSpace; -5 ). Ein einfaches und effizientes statistisches Verfahren wurde genutzt, um drei bedeutsame SNPs zu identifizieren. Zusammenfassung: Die Tunesische Bevölkerung zeigte eine gegenüber der Europäischen unterschiedliche Haplotypstruktur des ACE-Gens, und es wurden drei bedeutsame SNPs identifiziert. Diese werden für spätere Assoziationsstudien bei Tunesischen und anderen Nordafrikanischen Populationen hilfreich sein. Resumen Antecedentes: El enzima convertidor de la angiotensina (ECA) es un gen candidato en la etiología de varias enfermedades comunes. El estudio de la estructura haplotípica de este gen es de interés en diagnóstico y farmacogenómica. Objetivos: El estudio investigó el perfil haplotípico de los polimorfismos de nucleótidos simples (SNPs) dentro del gen ECA en la población de Túnez, y lo comparó con otras poblaciones. Se identificaron tres importantes SNPs para su futuro uso en estudios de asociación. Sujetos y métodos: Se tiparon cinco SNPs (rs1800764, rs4291, rs4309, rs4331, rs4340), que cubren una región de 15,6 kb del gen ECA, utilizando PCR-RFLP en una muestra de 100 sujetos sanos. Resultados: Todos los SNPs fueron polimórficos y estaban en equilibrio de Hardy-Weinberg. Se identificaron un total de 21 haplotipos, pero solo ocho presentaban una frecuencia mayor de 1%. Los cuatro haplotipos más comunes presentaban una frecuencia acumulada del 87,4%. Se observó el fenómeno “Yin-Yang” (dos haplotipos mayores son complementarios en todos los sitios). El desequilibrio de ligamiento entre todos los pares de loci fue altamente significativo ( p -5 ). Se utilizó un procedimiento estadístico simple y eficiente para identificar tres SNPs importantes. Conclusión: La población de Túnez mostró una estructura haplotípica diferente de la europea para el gen ECA y se identificaron tres SNPs importantes, los cuales serán de gran ayuda en futuros estudios de asociación en poblaciones de Túnez y del norte de África. [ABSTRACT FROM AUTHOR]