Ephrin type-A receptor 2-antisense RNA1/2 promote proliferation and migration of MDA-MB-231 cells through -dependent Ras signaling pathway mediated by MAPK8/JNK1, MAPK9/JNK2-NFATC2/NFAT1 and JUND.

Ephrin type-A receptor 2 (EPHA2) is a receptor tyrosine kinase that is overexpressed in a variety of cancers, including breast cancer. EPHA2 expression may be causally related to tumorigenesis; therefore, it is important to understand how expression is regulated. We previously reported that EPHA2 antisense RNA (EPHA2-AS), a natural antisense transcript, is an important modulator of EPHA2 mRNA levels and hence production of EPHA2 protein.

EPHA2 antisense RNA modulates EPHA2 mRNA levels in basal-like/triple-negative breast cancer cells.

Ephrin type-A receptor 2 (EPHA2) is a receptor tyrosine kinase (RTK), whose over-expression has been observed in a variety of cancers, including breast cancer. EPHA2 expression may be causally related to tumorigenesis; therefore, it is important to understand how EPHA2 gene (EPHA2) expression is regulated. Here, we report that EPHA2 antisense RNA (EPHA2-AS), a natural antisense transcript, is an important modulator of EPHA2 mRNA levels.

[Non-coding Natural Antisense RNA: Mechanisms of Action in the Regulation of Target Gene Expression and Its Clinical Implications].

Recent advances in high-throughput technologies have revealed that 75% of the human genome is transcribed to RNA, whereas only 3% of transcripts are translated into proteins. Consequently, many long non-coding RNAs (lncRNAs) have been identified, which has improved our understanding of the complexity of biological processes. LncRNAs comprise multiple classes of RNA transcripts that regulate the transcription, stability and translation of protein-coding genes in a genome.

Regulatory non-coding RNAs in nervous system development and disease.

Recent evidence demonstrates that long non-coding RNAs (lncRNAs) regulate the expression of multiple genes in an epigenetic, transcriptional, or post-transcriptional manner. They are involved in various cellular phenomena, such as the recruitment of transcription factors, epigenetic chaperoning, control of alternative splicing, mRNA stability and translational activity, as well as acting as decoys against microRNAs. In this review, we summarize the pivotal roles of lncRNAs in regulation of the gene expression involved in neural cell differentiation, synaptogenesis and synaptic plasticity in the central nervous system (CNS).

A guinea pig gene with antiviral activity against human influenza virus infection.

We previously reported a natural antisense (AS) RNA as an important modulator of human interferon-Alpha1 () mRNA levels. Here, we identified the guinea pig () gene to enable a proof-of-concept experiment to be performed to confirm that the AS-mRNA regulatory axis exerts control over innate immunity. We selected a guinea pig model system for influenza virus infection because encode a functional gene, an important anti-viral effector in the type I interferon pathway.

Pathogen-associated regulatory non-coding RNAs and oncogenesis.

Among all new cancer cases in 2012, on average, 15.4% were caused by or oncoviruses, including Epstein-Barr virus, human papillomavirus, , , Kaposi sarcoma-associated herpesvirus and human T-lymphotropic virus. These pathogens encode a variety of non-coding RNAs, which are important cofactors for oncogenesis.

Post-transcriptional inducible gene regulation by natural antisense RNA.

Accumulating data indicate the existence of natural antisense transcripts (asRNAs), frequently transcribed from eukaryotic genes and do not encode proteins in many cases. However, their importance has been overlooked due to their heterogeneity, low expression level, and unknown function. Genes induced in responses to various stimuli are transcriptionally regulated by the activation of a gene promoter and post-transcriptionally regulated by controlling mRNA stability and translatability.

Interleukin-1β induces tumor necrosis factor-α secretion from rat hepatocytes.

Aim: Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine involved in various inflammatory diseases. The only production of TNF-α in the liver is thought to be from hepatic macrophages known as Kupffer cells, predominantly in response to bacterial lipopolysaccharide (LPS).

Methods: Primary cultured rat hepatocytes were used to analyze TNF-α expression in response to the pro-inflammatory cytokine, interleukin-1β (IL-1β).

Stabilization of human interferon-α1 mRNA by its antisense RNA.

Antisense transcription is a widespread phenomenon in the mammalian genome and is believed to play a role in regulating gene expression. However, the exact functional significance of antisense transcription is largely unknown. Here, we show that natural antisense (AS) RNA is an important modulator of interferon-α1 (IFN-α1) mRNA levels.

Regulation of inducible gene expression by natural antisense transcripts.

Natural antisense transcripts are frequently transcribed from many genes in eukaryotes. Although natural antisense transcripts have been recognized for a long time, their importance has been overlooked due to their heterogeneity, low expression level, and unknown function. Genes induced in responses to various external stimuli are transcriptionally regulated by the activation of a gene promoter and post-transcriptionally regulated by controlling mRNA stability and translatability.

Nuclear and cytoplasmic effects of human CRM1 on HIV-1 production in rat cells.

The human immunodeficiency virus type 1 (HIV-1) regulatory protein, Rev, mediates the nuclear export of unspliced gag and singly spliced env mRNAs by bridging viral RNA and the export receptor, CRM1. Recently, rat CRM1 was found to be less efficient than human CRM1 in supporting Rev function in rats. In this study, to understand the role of CRM1 in HIV propagation, the mechanism underlying the function of human and rat CRM1 in HIV-1 replication was investigated in rat cells.

Novel cis-active structures in the coding region mediate CRM1-dependent nuclear export of IFN-α 1 mRNA.

We recently reported the chromosome region maintenance 1 (CRM1)-dependent nuclear export of intron-less human interferon-α1 (IFN-α1) mRNA, which encodes a main effecter of host innate immunity. We show that the coding region of IFN-α1 mRNA forms novel secondary structures that are responsible for the CRM1-dependent export of the transcript. Deletion-mutagenesis, in vivo export assays, and computer analyses of the folding potentials of export-competent fragments revealed the presence of a domain, termed the conserved secondary structure (CSS), comprising two adjacent putative stable stem-loop structures (nt 208-452).

Halogenated analogs of 1'-acetoxychavicol acetate, Rev-export inhibitor from Alpinia galanga, designed from mechanism of action.

In the course of search for the robust analogs of 1'-acetoxychavicol acetate (ACA, 1), the Rev-export inhibitor from the medicinal plant Alpinia galanga, we clarified formation of the quinone methide intermediate ii to be essential for exerting the inhibitory activity of 1. Based on this mechanism of action, the rational design from the MO calculation of the conclusive activation energy to ii resulted in the four halogenated analogs with more potent activity than ACA (1). In particular, the difluoroanalog 20d exhibited approximately four-fold potent activity as compared with 1.

Bioisostere of valtrate, anti-HIV principle by inhibition for nuclear export of Rev.

Rational design by the MO calculation disclosed 5,6-dihydrovaltrate (2) as the bioisostere of valtrate (1), the Rev-export inhibitor with anti-HIV activity. The synthesis of 2 was accomplished by ingenious use of asymmetric Diels-Alder reaction and stereoselective epoxidation associated with the adjacent hydroxyl group. Because of similar biological potency to 1, the analog 2 should be recognized as a promising scaffold for new anti-HIV agents with an unprecedented mechanism of action, inhibition for nuclear export of Rev protein, in the conventional remedy.

Nucleocytoplasmic transport of luciferase gene mRNA requires CRM1/Exportin1 and RanGTPase.

Human immunodeficiency virus type 1 Rev (regulator of the expression of the virion) protein was shown to reduce the expression level of the co-transfected luciferase reporter gene (luc+) introduced to monitor transfection efficiency. We studied the mechanism of the inhibitory Rev effect. The effect, caused by nuclear retention of luc+ mRNA, was reversed if rev had a point mutation that makes its nuclear export signal (NES) unable to associate with cellular transport factors.

New Rev-export inhibitor from Alpinia galanga and structure-activity relationship.

Bioassay-guided separation by use of the fission yeast expressing NES of Rev, an HIV-1 viral regulatory protein, disclosed 1'-acetoxychavicol acetate (ACA, 1) as a new inhibitor for nuclear export of Rev from the roots of Alpinia galanga. Both analysis for mechanism of action with biotinylated probe (2) and several synthesized analogs established crucial portions in 1 for Rev-export inhibitory activity.

Natural antisense transcript stabilizes inducible nitric oxide synthase messenger RNA in rat hepatocytes.

Unlabelled: During inflammation, inducible nitric oxide synthase (iNOS) is induced to generate the important mediator nitric oxide (NO). Interleukin 1beta (IL-1beta) induces iNOS messenger RNA (mRNA), iNOS protein, and NO in rat hepatocytes. We found that the stability of iNOS mRNA changed during the induction and that the antisense (AS) strand corresponding to the 3'-untranslated region (3'UTR) of iNOS mRNA was transcribed from the iNOS gene.

CRM1-dependent, but not ARE-mediated, nuclear export of IFN-alpha1 mRNA.

While the bulk of cellular mRNA is known to be exported by the TAP pathway, export of specific subsets of cellular mRNAs may rely on chromosome region maintenance 1 (CRM1). One line of evidence supporting this hypothesis comes from the study of mRNAs of certain early response genes (ERGs) containing the adenylate uridylate-rich element (ARE) in their 3' untranslated regions (3' UTRs). It was reported that HuR-mediated nuclear export of these mRNAs was CRM1-dependent under certain stress conditions.