Disease relevance of GFER

• About 35 related elements were found to be distributed on all human chromosomes except 16, 17, and Y. Sequence comparisons with Mo-MuLV and various type C-related HERVs suggest that despite a proline primer-binding site this novel HERV element, now named HERV-IP-T47D, can be assigned to one family together with known HERV-I elements [1].
• Quantitative mRNA analysis revealed significantly increased ALR expression in cirrhosis compared with normal liver tissue [2].
• Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma [2].
• The dose-dependent stimulation of DNA synthesis of HepG2 hepatoma cells by HPO-205 demonstrated its similar biological activity with HPO in vitro [3].
• Here we show that the human lymphotropic herpesvirus Epstein-Barr virus (EBV) transcriptionally activates the env gene of an endogenous retrovirus, HERV-K18, that possesses SAg activity [4].

High impact information on GFER

• SAg activity was demonstrated by MHC class II dependent preferential activation of TCRVB13 T cells in response to murine B cells transfected with the HERV-K18 env gene [4].
• Here we show that duplication chromosomes exist in population samples by detecting Y-chromosomal short tandem repeat (YSTR) allele duplications within the AZFa region, and by showing that two chromosomes carrying these duplicated alleles contain a third junction-specific HERV sequence [5].
• The effect of bidentate 3-hydroxypyridin-4-one (HPO) iron chelators on cell cycle arrest with subsequent cycle synchronization has been compared with that of the hexadentate desferrioxamine (DFO) in K562 and Daudi cells [6].
• The central core of the plant enzyme (AtErv1) exhibits all of the characteristic features of the Erv1/Alr protein family, including a redox-active YPCXXC motif, noncovalently bound FAD, and sulfhydryl oxidase activity [7].
• In this study we identified a likely candidate for the first mitochondrial flavin-linked sulfhydryl oxidase of the Erv1-type from a photosynthetic organism [7].

Chemical compound and disease context of GFER

• The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20) [8].

Biological context of GFER

• Analysis of the structure and expression of the augmenter of liver regeneration (ALR) gene [9].
• The ALR gene maps to the mouse chromosome 17, in a region syntenic with human chromosome 16, where the T/t region has also been mapped [9].
• The mapping of mouse and human ALR genes on mouse and human chromosomes was then completed [9].
• RESULTS: The protein coding portion of the mouse ALR gene is comprised of three exons, the first containing the 5' untranslated sequence and the initial 18 bases after the ATG translation initiation codon, the second exon encompasses 198 bases, and the third exon contains the remaining portion of the protein coding sequence [9].
• MATERIALS AND METHODS: Standard molecular biology approaches have been used to determine the genomic structure of the ALR gene in the mouse, and to characterize the ALR transcript and its protein product [9].

Anatomical context of GFER

• The ERV/ALR sulfhydryl oxidase domain is a versatile module adapted for catalysis of disulfide bond formation in various organelles and biological settings [10].
• CONCLUSIONS: ALR appears to be a protein with important physiologic properties, not exclusively limited to liver regeneration, with roles that are involved in the synthesis or stability of the nuclear and mitochondrial transcripts that are present in actively regenerating cells, particularly the germ cells of the testes [9].
• Rat, mouse, and human ALR genes (and protein products) were found to be highly conserved and preferentially expressed in the testis and in the liver [9].
• The level of MAPK (Mitogen-activated protein kinase) phosphorylation by Western blot analysis revealed that HPO-205 might have the stronger activity of stimulating hepatic cell proliferation than that of HPO [3].
• The yeast and human mitochondrial sulfhydryl oxidases of the Erv1/Alr family have been shown to be essential for the biogenesis of mitochondria and the cytosolic iron sulfur cluster assembly [7].

Associations of GFER with chemical compounds

• AIM: To isolate a novel isoform of human HPO (HPO-205) from human fetal liver Marathon-ready cDNA and characterize its primary biological function [3].
• QSOX is an ancient fusion of thioredoxin domains and an FAD-binding module, ERV1/ALR [11].
• In a resistance-induced clone, HPO1, the affinity of PBP1 for amoxicillin was reduced [12].
• In contrast, ALR revealed no effects on phase II reactions (glutathione/oxidized glutathione, UDP-glucuronyltransferase conjugation) [13].
• All three ligands show the 3-hydroxy-2(1H)-pyridinone (HPO) groups attached as sidearms to a polyaza fragment, which is a macrocyclic framework in the case of L1 and L2 while it is an open chain in the case of L3 [14].

Enzymatic interactions of GFER

• We have determined by X-ray crystallography the structure of AtErv1, an ERV/ALR enzyme that contains a Cys-X(4)-Cys shuttle disulfide and oxidizes thioredoxin in vitro, and compared it to ScErv2, which has a Cys-X-Cys shuttle and does not oxidize thioredoxin at an appreciable rate [10].

Other interactions of GFER

• A redox pathway (Mia40p and Erv1p) mediates the import of intermembrane space proteins such as the small Tim proteins, Cox17p, and Cox19p, which have disulfide bonds [15].

Analytical, diagnostic and therapeutic context of GFER

• Expression analysis of ALR in total liver protein extracts by Western blotting showed mainly dimeric ALR protein [2].
• METHODS AND RESULTS: ALR expression in normal and cirrhotic human livers with various underlying diseases as well as in tissue samples of hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) was analysed by immunohistochemistry and quantitative reverse transciptase-polymerase chain reaction (RT-PCR) [2].
• Here we show by in situ hybridization, that HERV-PTN fusion transcripts are expressed in malignant trophoblasts (i.e. choriocarcinoma) and in the proliferative and in the invasive trophoblasts of gestational trophoblastic tissue [16].
• Direct amplification of proviral structures from single chromosomes by using chromosomal flanking primers was performed by long PCR for HERV-K(C7) and HERV-K(C19) and for type 1 proviruses HERV-K10 and HERV-K18 from chromosomes 5 and 1, respectively [17].
• The human endogenous retrovirus type II (HERVII) family of HERV genomes has been found by Southern blot analysis to be characteristic of humans, apes, and Old World monkeys [18].

References