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)

A series of antisense pentadecamers complementary to a variety of target sequences between the cap and AUG initiation codon regions of c-myc mRNA was synthesized and used to treat human promyelocytic leukemia HL-60 cells. The sensitivity of the cap-region sequences to antisense inhibition of c-myc p65 expression was two to three times that of the original initiation codon antisense sequence. The other target sequences downstream of the cap and up to the AUG initiation codon were comparable to the initiation codon sequence, except that the first splice junction was slightly more sensitive. At the primary initiation codon target, a dodecamer was about half as effective as the original pentadecamer, whereas an octadecamer was about twice as effective. The observation of variation in antisense efficacy as a function of target location in c-myc mRNA may represent a combination of the effects of hybrid arrest, RNase H attack, and interference in RNA processing. Alternatively, the most sensitive targets might be those that are the most exposed in the secondary and tertiary structure of c-myc mRNA.
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PMID:Walking along human c-myc mRNA with antisense oligodeoxynucleotides: maximum efficacy at the 5' cap region. 199 45

A 28-mer morpholino oligonucleotide analog was designed to hybridize to 8 bases of intron 1 and extend 2 bases beyond the translation initiation codon in exon 2 of the unspliced c-myc RNA transcript. Delivery of this compound into human chronic myeloid leukemia KYO1 cells, by streptolysin O permeabilization, resulted in almost total ablation of the 65 kDa c-MYC protein expression for at least 24 hours after treatment. An unexpected band with SDS-PAGE electrophoretic mobility indicating a protein of about 47 kDa was apparent on the 24-hour western blots that were developed using antibodies that recognize MYC protein C terminal epitopes. No inhibition of the approximately 2400 nt c-myc mRNA expression was observed by northern hybridization, a result of the inability of morpholino analogs to direct the activity of ribonuclease H. In fact, high molecular weight c-myc RNA species were found to have accumulated in antisense-treated KYO1 cells. Control sense and scrambled antisense morpholino analogs did not inhibit MYC protein expression or induce the appearance of the anomalous RNA and protein bands. Molecular analyses by RT-PCR and sequencing revealed that the morpholino antisense effector had (1) inhibited splicing of the c-myc pre-mRNA, (2) induced missplicing of the pre-mRNA, and (3) inhibited translation of normal spliced c-myc mRNA. Identical results were obtained with acute promyelocytic leukemia, acute lymphoblastic leukemia, and histiocytic lymphoma cell lines.
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PMID:Antisense morpholino oligonucleotide analog induces missplicing of C-myc mRNA. 1035 27