Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.4 (RNase H)
 2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RNase H has been clearly implicated in vitro in mediating some antisense effects. In vivo evidence is limited to experiments performed in Xenopus oocytes in which antisense oligonucleotides are microinjected. In other mammalian cell systems scant data have been obtained to support or deny a role for RNase H as an antisense mediator in vivo. These experiments were designed to test the hypothesis that RNase H mediates the MYC antisense-induced reduction in MYC protein observed in the human monocytic leukemia cell line U937. A bacterial RNase H-containing episomal replicon was constructed and stable transfectants were obtained which expressed E coli RNase H in their cytoplasm at a 10-fold higher level than endogenous RNase H. These cells failed to demonstrate heightened sensitivity to MYC antisense (phosphorothioate, end capped and phosphodiester) compared with untransfected or E coli RNase H antisense transfected cells. PCR analysis of each transfectant treated and untreated with MYC antisense failed to demonstrate the appearance of truncated MYC mRNA. These results do not support a role for RNase H in the mediation of MYC antisense-induced MYC protein reduction and growth inhibition in U937 cells.
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PMID:Effect of over-expression of bacterial ribonuclease H on the utility of antisense MYC oligodeoxynucleotides in the monocytic leukemia cell line U937. 838 12

The microRNA (miRNA) cluster miR-17-92 is oncogenic and represents a valuable therapeutic target in c-MYC (MYC)-driven malignancies. Here, we developed novel LNA gapmeR antisense oligonucleotides (ASOs) to induce ribonuclease H-mediated degradation of MIR17HG primary transcripts and consequently prevent biogenesis of miR-17-92 miRNAs (miR-17-92s). The leading LNA ASO, MIR17PTi, impaired proliferation of several cancer cell lines (n = 48) established from both solid and hematologic tumors by on-target antisense activity, more effectively as compared with miR-17-92 inhibitors. By focusing on multiple myeloma (MM), we found that MIR17PTi triggers apoptosis via impairment of homeostatic MYC/miR-17-92 feed-forward loops (FFLs) in patient-derived MM cells and induces MYC-dependent synthetic lethality. We show that alteration of a BIM-centered FFL is instrumental for MIR17PTi to induce cytotoxicity in MM cells. MIR17PTi exerts strong in vivo antitumor activity in nonobese diabetic severe combined immunodeficient mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetic profiles in nonhuman primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies.
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PMID:Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92. 3019 Mar 51