Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.27.1 (RNase)
 16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kaposi's sarcoma-associated herpesvirus (KSHV) is a recently discovered human gamma herpesvirus strongly implicated in AIDS-related neoplasms. We report here the identification in the KSHV genome of a gene for a protein designated K-bZIP and belonging to the basic-leucine zipper (bZIP) family of transcription factors. K-bZIP shows significant homology to BZLF1, which plays a key role in the replication and reactivation of Epstein-Barr virus. K-bZIP is a homodimerizing protein of 237 amino acids with a prototypic bZIP domain at the C terminus. The N-terminal portion of K-bZIP is derived from the K8 open reading frame which, through in-frame splicing, adjoins the ZIP domain. This structure was revealed by rapid analysis of cDNA ends, followed by cloning of the entire cDNA. A 1.35-kb transcript encoding K-bZIP was detected in BCBL-1 cells treated with 12-O-tetradecanoylphorbol-13-acetate. The synthesis of this transcript was blocked by the protein synthesis inhibitor cycloheximide but not by the viral DNA synthesis inhibitor phosphonoacetate, a result which classifies it as an early lytic gene. RNase protection analysis further mapped the major transcription start site for the 1.35-kb K-bZIP mRNA and identified two other splice variants which encode proteins with the N-terminal portion of K-bZIP but lacking the C-terminal ZIP domain. Full-length K-bZIP forms dimers with itself, and the C terminus encompassing the ZIP domain is required for this process. Our studies set the stage for understanding the role of K-bZIP in the replication and reactivation of the KSHV genome.
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PMID:Kaposi's sarcoma-associated herpesvirus encodes a bZIP protein with homology to BZLF1 of Epstein-Barr virus. 997 70

Rta, mainly encoded by open reading frame 50 (ORF50), is the product of an immediate-early gene of human herpesvirus-8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus. Rta is a transcriptional activator that is both necessary and sufficient to disrupt viral latency and activate the expression of downstream viral lytic genes. We report that ectopically expressed Rta protein could also activate the rta promoter on a reporter plasmid up to 144-fold, both in latently infected B cells and in uninfected epithelial cells, and that this activation was dose-dependent. Furthermore, by analysing the 5' untranslated region using ribonuclease protection assays, we demonstrated that transfection of an Rta expression plasmid into latently infected cells activated the expression of rta transcripts from endogenous viral genomes. We propose that auto-activation of the immediate-early gene, rta, is an important strategy for HHV-8 to effectively respond to environmental stimuli and maximally activate the virus lytic cycle.
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PMID:Auto-activation of the rta gene of human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus. 1108 35

Our demonstration of a 19kDa anti-Kaposi's sarcoma (KS) ribonuclease (RNase) in urine from a non-pregnant female may provide at least part of the explanation for the low incidence of KS in human females. N-terminal sequence analysis and isoelectric focusing of the purified RNase, coupled with the very low levels of anti-KS activity noted for recombinant forms of human eosinophil derived neurotoxin and human eosinophil cationic protein, suggest that the 19kDa enzyme is an eosinophilic protein whose potent anti-KS activity is dependent upon post-translational modifications that occur only in human cells.
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PMID:Human non-pregnancy ribonuclease with anti-Kaposi's sarcoma activity. 1180 46

Tissue expression of CC and CXC chemokines and chemokine receptors was investigated in 6 cases of classic non-AIDS Kaposi sarcoma (KS) using immunohistochemistry and RNase protection assay (RPA). Immunostaining of frozen sections of KS skin biopsies revealed that KS spindle cells express several chemokine receptors. In KS nodules, almost all KS spindle cells were intensely stained for CXCR4 and CCR5. Other chemokine receptors as CCR1, CXCR3, and CCR2 were also detected in the large majority of KS spindle cells. A minority of KS spindle cells also expressed the fractalkine receptor (FK-R) CX3CR1. The immunohistochemical findings were confirmed at RNA level. In fact, the RNase protection assay (RPA) revealed in 6 of 6 cases the presence of consistent amounts of mRNAs for CXCR4 and CCR1 and in 5 of 6 cases also for CCR5 and CXCR3. Expression of chemokine receptors by KS cells was associated with chemokine production within the lesions. In the same cases, RPA demonstrated the presence of mRNAs for MCP-1, RANTES, IP-10, MIP-1alpha, and MIP-1beta. Chemokine-producing cells, as detected by immunohistochemistry, were mainly spindle-shaped cells resembling tissue macrophages outside KS lesions and some scattered cells (<5%) present within KS nodules. The demonstration of chemokine receptors in KS cells raises the possibility that recruitment of KS cells in response to locally produced chemotactic stimuli may be one of the events involved in the pathogenesis of Kaposi sarcoma.
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PMID:In situ study of chemokine and chemokine-receptor expression in Kaposi sarcoma. 1450 Dec 86

Several commercial preparations of human chorionic gonadotropin (hCG) have been tested as therapy for Kaposi's sarcoma (KS) in clinical trials, but with discordant outcomes. We also have found dramatic differences in the cytotoxic effects of four different commercial hCG preparations on an established KS cell line, KSIMM. A co-purified moiety (ies) present in these preparations may explain these differences. The eosinophil-derived neurotoxin ribonuclease, extended with four extra residues ((-4)EDN), has been suggested to be the putative anti-KS compound in the hCG preparations, being specifically recognized by the cells through its N terminal extension. We therefore synthesized a 16-residue peptide (MSLHV-NT12 EDN), made to resemble the active recognition sequence of (-4)EDN. MSLHV-NT12 EDN displays a dose-dependent cytotoxic effect on KSIMM (killing 50% of the cells at 9 microg/ml). The cytotoxic effect is specific for KS cells, MSLHV-NT12 EDN being harmless even at 100 microg/ml for a melanoma cell line (SK-MEL-28) or for normal human fibroblasts. We also demonstrated that MSLHV-NT12 EDN induces apoptosis in KSIMM cells. In conclusion, MSLHV-NT12 EDN is a specific proapoptotic substance for KS cells, which warrants further investigation into its in vivo effects.
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PMID:A synthetic peptide derived from the human eosinophil-derived neurotoxin induces apoptosis in Kaposi's sarcoma cells. 1527 5

Human herpesvirus-8 (HHV-8, also called Kaposi's sarcoma-associated herpesvirus) infectious cycle can be divided into latent and lytic phases. During the latent phase viral gene expression is reduced to a minimum, while during the lytic phase, numerous genes are expressed sequentially. The development of an RNase Protection Assay (RPA) is described that allows the detection and quantitation of three latent (ORFs 71-72-73) and three lytic (ORFs 74-K4-K2) HHV-8 genes as well as two cellular housekeeping gene transcripts (glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cyclophilin) for normalization purposes is described. The RPA was validated using 293T cells transfected with corresponding HHV-8 expression vectors and using resting and phorbol ester-butyric acid-activated BC-3 and BCBL-1 cells. The results obtained indicate that this RPA is specific, sensitive and allows for the simultaneous monitoring of HHV-8 latent and lytic genes expression. HHV-8-RPA is therefore a useful technique to monitor the status of HHV-8 infection in infected cells (latent versus lytic) by comparing and quantitating multiple viral transcripts expression from a single RNA sample.
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PMID:Multiplex detection and quantitation of latent and lytic transcripts of human herpesvirus-8 using RNase Protection Assay. 1548 14

The K15 gene product of Kaposi's sarcoma-associated herpesvirus (KSHV) is a transmembrane protein that is encoded by the last open reading frame of the KSHV genome. The K15 protein has been implicated in modulation of B-cell signal transduction and activation of the Ras/mitogen-activated protein kinase and NF-kappaB signal transduction pathways. Here we report the identification of the transcriptional start site of the full-length K15 gene in KSHV-positive BCBL-1 cells. We have mapped the K15 transcriptional start site to a position 152 nucleotides upstream from the translation start site by rapid amplification of cDNA ends and RNase protection assays. We have also characterized the K15 promoter element. To analyze the cis-acting elements necessary to regulate K15 gene expression, a series of 5' promoter deletion constructs were generated and subcloned upstream of the luciferase reporter gene. Transcriptional assays with these mutant promoters demonstrated that chemical induction in latently infected KSHV-positive BCBL-1 cells activated K15 transcription. In addition, K15 promoter transactivation was also mediated by the viral immediate-early protein Orf50/Rta, suggesting that the K15 gene is actively transcribed during lytic replication.
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PMID:Transcriptional regulation of the Kaposi's sarcoma-associated herpesvirus K15 gene. 1641 16

Regulation of messenger RNA (mRNA) stability plays critical roles in controlling gene expression, ensuring transcript fidelity, and allowing cells to respond to environmental cues. Unregulated enhancement of mRNA turnover could therefore dampen cellular responses to such signals. Indeed, several herpesviruses instigate widespread destruction of cellular mRNAs to block host gene expression and evade immune detection. Kaposi's sarcoma-associated herpesvirus (KSHV) promotes this phenotype via the activity of its viral SOX protein, although the mechanism of SOX-induced mRNA turnover has remained unknown, given its apparent lack of intrinsic ribonuclease activity. Here, we report that KSHV SOX stimulates cellular transcriptome turnover via a unique mechanism involving aberrant polyadenylation. Transcripts in SOX-expressing cells exhibit extended poly(A) polymerase II-generated poly(A) tails and polyadenylation-linked mRNA turnover. SOX-induced polyadenylation changes correlate with its RNA turnover function, and inhibition of poly(A) tail formation blocks SOX activity. Both nuclear and cytoplasmic poly(A) binding proteins are critical cellular cofactors for SOX function, the latter of which undergoes striking nuclear relocalization by SOX. SOX-induced mRNA turnover therefore represents both a novel mechanism of host shutoff as well as a new model system to probe the regulation of poly(A) tail-stimulated mRNA turnover in mammalian cells.
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PMID:Aberrant herpesvirus-induced polyadenylation correlates with cellular messenger RNA destruction. 1946 99

The Kaposi's sarcoma-associated herpesvirus protein SOX (shut off and exonuclease) and its Epstein-Barr virus homolog, BGLF5, are active during the early lytic phase and belong to the alkaline nuclease family. Both proteins have been shown to be bifunctional, being responsible for DNA maturation as well as host shutoff at the mRNA level. We present the crystal structure of SOX determined at 1.85 A resolution. By modeling DNA binding, we have identified catalytic residues that explain the preferred 5'-exonuclease activity of the alkaline nucleases. The presence of a crevice suitable for binding duplex DNA supports a role for herpes alkaline nucleases in recombination events preceding packaging of viral DNA. Direct interaction with dsDNA is supported by oligonucleotide binding data. Mutations specifically affecting host shutoff map to a surface region of the N-terminal domain, implying an essential role in protein-protein interactions, and link the RNase activity of the enzyme to mRNA degradation pathways.
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PMID:Crystal structure of the shutoff and exonuclease protein from the oncogenic Kaposi's sarcoma-associated herpesvirus. 1984 64

The early lytic phase of Kaposi's sarcoma herpesvirus infection is characterized by viral replication and the global degradation (shutoff) of host mRNA. Key to both activities is the virally encoded alkaline exonuclease KSHV SOX. While the DNase activity of KSHV SOX is required for the resolution of viral genomic DNA as a precursor to encapsidation, its exact involvement in host shutoff remains to be determined. We present the first crystal structure of a KSHV SOX-DNA complex that has illuminated the catalytic mechanism underpinning both its endo and exonuclease activities. We further illustrate that KSHV SOX, similar to its Epstein-Barr virus homologue, has an intrinsic RNase activity in vitro that although an element of host shutoff, cannot solely account for the phenomenon.
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PMID:Crystal structure of a KSHV-SOX-DNA complex: insights into the molecular mechanisms underlying DNase activity and host shutoff. 2142 61


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