Genetic variations in tumor necrosis factor related apoptosis-inducing ligand receptor-1 (TRAIL-R1) gene and the susceptibility to B cell nonhodgkin lymphoma in Egypt

BACKGROUND: Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells. OBJECTIVE: to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians. METHODS: Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls. RESULTS: The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR = 1.76; 95%CI = 1.01–3.22 and OR = 1.89; 95%CI = 1.01–3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR = 3.57; 95%CI = 1.29–9.84). The risk conferred by -C626G SNP increased for DLBCL (OR = 3.39, 95% CI: 1.61–7.16). CONCLUSION: TRAIL-R1–C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population.

The impact of R1and R3a genes on tuber resistance to late blight of the potato breeding clones

Potato breeding clones were evaluated for resistance to late blight (agent Phytophthora infestans) using tuber inoculation tests and for presence of the resistance alleles of R1 and R3a genes in polymerase chain reaction tests. Among clones tested those expressing high, moderate and low resistance were identified. The data were analysed for the impact of R1 and R3a genes on tuber resistance to late blight in tested plant material. In previous evaluations performed on smaller amount of clones the tuber resistance levels significantly depended on presence/absence of the resistance allele of R3a gene and did not depend on presence of R1 gene allele. In the current study the statistical analyses did not prove the significant difference in resistance levels depending on presence of the resistance alleles, neither of R1 gene, nor of R3a gene. Tuber resistant clones bearing R3a gene resistance alleles still noticeably prevailed over the clones bearing the alleles of R1 gene as well as over the clones bearing the no resistance alleles of both genes. In several cases the resistance of clones with detected resistance allele of R1 gene was higher compared to those derived from the same crosses and showing amplification of the allele of R3a gene or those with no resistance alleles. Clones accumulating the resistance alleles of both (R1 and R3a) genes expressed high tuber resistance accompanied by necrotic reaction.

Characterization of Synonymous Codon Usage in the R1 Gene of Duck Enteritis Virus

In this paper, a corresponding analysis of the codon usage bias in the large subunit of ribonucleotide reductase (R1), encoded by UL39 gene from duck enteritis virus (DEV) CHv strain (Assigned Accession No.: EU071042) and 33 other reference herpesviruses was performed by using CAI, CHIPS and CUSP program of EMBOSS, aims to provide a basis for understanding the evolution and pathogenesis of DEV and for selecting appropriate host expression systems. The results showed that codon usage bias of DEV R1 gene strongly preferred to the synonymous with A and T at the third codon position; the phylogentic analysis revealed that DEV had a close evolutionary relationship with the avian Alphaherpesvirinae. In addition, the codon usage bias of DEV R1 gene was compared with those of E.coli, yeast and human. There are 17 codons showing distinct usage differences between DEV and E.coli, 13 codons between DEV and yeast, 20 codons between DEV and human. Therefore, the yeast expression system is more suitable for the target gene’s expression. The extent of codon usage bias in the DEV R1 gene was highly correlated with the gene expression level, therefore the results may provide useful information for the study of classification and function of the target gene.

Involvement of Egr-1 in HGF-induced elevation of the human 5α-R1 gene in human hepatocellular carcinoma cells

Steroid 5α-reductase 1 (5α-R1), a key enzyme in the conversion of steroids into their respective 5α-reduced derivatives, plays a key role in some hormone-dependent tumours and is abundant in the liver, although it is also widely distributed throughout the body. HGF (hepatocyte growth factor) is a pleiotropic cytokine/growth factor involved in the progression of hepatocellular carcinoma. In the present paper, we report the stimulatory effect of HGF on human 5α-R1 transcription in hepatocellular carcinoma cells. Pre-treatment with actinomycin D or cycloheximide blocked the up-regulation of 5α-R1 mRNA expression by HGF, indicating that the increased level of 5α-R1 mRNA expression is regulated by transcriptional activation and was dependent on de novo protein synthesis. Functional analysis of the 5′-flanking region of the 5α-R1 gene by transfection analysis showed that the −79 to −50 region functioned as the HGF-responsive region. Mutagenesis and electrophoretic mobility-shift assays demonstrated that induction of 5a-R1 by HGF is mediated by an Egr-1 (early growth-response gene 1)-binding site at −60/−54. In addition, overexpression of Egr-1 was sufficient to transactivate 5α-R1 promoter activity, and knockdown of Egr-1 with gene-specific small interfering RNA resulted in inhibition of HGF-induced up-regulation of endogenous 5α-R1 expression. These data provide the first evidence that HGF stimulates 5α-R1 expression through up-regulation of the transcription factor Egr-1, thus suggesting the possibility that regulation of steroid metabolism by HGF represents a mechanism for high risk of hepatocellular carcinogenesis in males.

The Onset of Labor Alters Corticotropin-Releasing Hormone Type 1 Receptor Variant Expression in Human Myometrium: Putative Role of Interleukin-1β

CRH targets the human myometrium during pregnancy. The efficiency of CRH actions is determined by expression of functional receptors (CRH-R), which are dynamically regulated. Studies in myometrial tissue biopsies using quantitative RT-PCR demonstrated that the onset of labor, term or preterm, is associated with a significant 2- to 3-fold increase in CRH-R1 mRNA levels. Detailed analysis of myometrial CRH-R1 mRNA variants showed a decline of the pro-CRH-R1 mRNA encoding the CRH-R1β variant during labor and increased mRNA levels of CRH-R1d mRNA. Studies in myometrial cells identified IL-1β as an important regulator of myometrial CRH-R1 gene expression because prolonged treatment of myometrial cells with IL-1β (1 ng/ml) for 18 h induced expression of CRH-R1 mRNA levels by 1.5- to 2-fold but significantly attenuated CRH-R1β mRNA expression by 70%. In contrast, IL-1β had no effect on CRH-R1d mRNA expression. Studies using specific inhibitors suggest that ERK1/2, p38 MAPK, and downstream nuclear translocation of nuclear factor-κB mediate IL-1β effects on myometrial CRH-R1 gene. However, the increased CRH-R1 mRNA expression was associated with a dampening of the receptor efficacy to activate the adenylyl cyclase/cAMP signaling cascade. Thus, our findings suggest that IL-1β is an important regulator of CRH-R1 expression and functional activity, and this interaction might play a role in the transition of the uterus from quiescence to active contractions necessary for the onset of parturition.