ABSTRACT
Flaviviruses are single-stranded positive sense RNA enveloped viruses. The flavivirus genus includes important human pathogens such as dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and Murray Valley encephalitis virus (MVEV). In addition to the viral proteins and viral genomic RNA, flaviviruses produce at least two functional non-coding RNAs derived from the 3' untranslated region (3'UTR), the subgenomic flavivirus RNA (sfRNA) and a putative WNV miRNA (KUN-miR-1). In this review we summarize published data from studies with WNV, YFV, DENV, JEV, and MVEV on sfRNA production following incomplete degradation of the viral genomic RNA by the cellular 5'-3' exoribonuclease 1 (XRN1), RNA structural elements involved in stalling XRN1 to generate sfRNA, and functions of sfRNA in modulating cellular mRNA decay and RNAi pathways as well as in modulating anti-viral type I interferon response. In addition, we also summarize data on the mechanisms of biogenesis of 3'UTR-derived KUN-miR-1 and its function in WNV replication in mosquito host, along with recent findings on a discovery of a second potential flaviviral miRNA vsRNA5, derived from the 3'UTR of DENV. This review thus summarizes the known mechanisms of generation and the functions of flaviviral 3'UTR-derived non-coding RNAs.
Subject(s)
3' Untranslated Regions , Flavivirus/physiology , Host-Pathogen Interactions , RNA, Viral/metabolism , Virus Replication , Animals , Culicidae , Exoribonucleases/metabolism , Flavivirus/genetics , Gene Silencing , Humans , Nucleic Acid Conformation , RNA Stability , RNA, Viral/chemistry , RNA, Viral/geneticsABSTRACT
Glutathione S-transferase P1-1 (GSTP1-1) is a multifunctional enzyme which protects the cell from the influence of genotoxic factors and apoptosis. Contemporary knowledge about the GSTP1 molecule structure and the enzyme functions are summarized in this review. Also P1 isoform is compared to other glutathione S-transferases and structure-function relationships are emphasized. Novel functions of GSTP1 in cell signaling modulation, NO storage and metabolism are highlighted in this paper.
Subject(s)
Glutathione S-Transferase pi/chemistry , Glutathione S-Transferase pi/physiology , Animals , Apoptosis/physiology , Catalysis , Humans , Models, Molecular , Nitric Oxide/metabolism , Signal Transduction/physiologyABSTRACT
Glutathione S-transferase P1 is a major phase II detoxification enzyme in most cell types. Aberrant expression of GSTP1 is associated with carcinogenesis and development of multidrug resistance. GSTP1 gene transcription is regulated by promoter methylation and by transcription factors. To elucidate the mechanisms responsible for the different levels of GSTP1 expression observed in Hbl-100 and BeWo cells we utilized truncated promoter constructs to compare the functional role of different promoter elements. We also identified transcription factors binding the responsive elements by electrophoretic mobility shift assay. The applied approaches provided the evidence that binding of transcription factors to ARE, CRE and NF-kappaB sites are responsible for the cell specific levels of GSTP1 expression in Hbl-100 and BeWo cells. It was also indicated that partial promoter methylation occurs in BeWo cells.
Subject(s)
Breast Neoplasms/genetics , Choriocarcinoma/genetics , Gene Expression Regulation, Enzymologic , Glutathione S-Transferase pi/genetics , Transcription, Genetic , Uterine Neoplasms/genetics , Blotting, Western , Cell Line, Tumor , DNA Methylation , Electrophoretic Mobility Shift Assay , Female , Humans , Polymerase Chain Reaction , Pregnancy , Promoter Regions, Genetic , Protein Binding , Transcription Factors/metabolismABSTRACT
Glutathione S-transferase P1-1 is the main phase II xenobiotic metabolism enzyme in human placenta. Low level of its gene expression and corresponding ineffective protection of fetus from toxic compounds is associated with pregnancy disorders such as preeclampsia and abnormalities of fetus development. It was previously reported that environmental radioactive contamination caused down-regulation of GSTP1 transcription in human placenta, but mechanisms responsible for such changes were unclear. In the present study we have found that observed changes in transcription of this gene are not caused by promoter methylation because GSTP1 promoter was not methylated in any of analyzed 91 placental samples. Regulation of GSTP1 by methylation or transcription factors was not previously studied in human placenta. Using "Gene Expression Atlas" online software the placental expression profile of transcription factors known to interact with GSTP1 promoter in other cell types, was identified. According to computer analysis the genes coding for GATA2, GATA3, Fos-B, Nrf3 and MafK transcription factors are highly expressed in human placenta, while genes coding for c-Fos, Juns, Mafs, ERbeta, RARalpha and NF-kappaB factors have moderate level of expression. Competitive EMSA provided the evidence that ARE and NF-kappaB-like sites specifically interacted with placental nuclear proteins. Among these proteins transcription factors AP-1 and NF-kappaB were identified using corresponding consensus oligonucleotides as competitors in EMSA.
