Altered mRNA splicing and inhibition of human E-selectin expression by an antisense oligonucleotide in human umbilical vein endothelial cells.

The Journal of Biological Chemistry
T P Condon, C F Bennett

Abstract

We have characterized the mechanism of action of an antisense oligodeoxynucleotide (ASO) targeting human endothelial leukocyte adhesion molecule, E-selectin. ISIS 4730, a 20-base ASO designed to be complementary to a region in the 3'-untranslated region (3'-UTR) of human E-selectin, is a potent and specific inhibitor of both mRNA and protein expression in human umbilical vein endothelial cells. Following treatment with ISIS 4730, a lower molecular weight mRNA (3300 bases) species was detected by Northern blot analysis with a corresponding decrease in the mature E-selectin transcript (3875 bases). The ASO-induced low molecular weight mRNA is stable and remains in the nucleus. We demonstrate that ISIS 4730 targets E-selectin pre-mRNA in the nucleus and promotes cleavage of the pre-mRNA at the hybridization site, resulting in prevention of splicing of the last intron. The change in molecular weight of the E-selectin transcript is the result of loss of the 3'-UTR due to ASO-mediated RNA cleavage and retention of the last intron. Cleavage of the E-selectin pre-mRNA appears to be due to endogenous RNase H or a related enzyme activity.

References

Jun 21, 1990·Biochimica Et Biophysica Acta·C Hélène, J J Toulmé
Mar 1, 1990·Journal of Biochemical and Biophysical Methods·J M CampbellE Wickstrom
Dec 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·M P BevilacquaM A Gimbrone
Jan 1, 1981·Annual Review of Biochemistry·R Breathnach, P Chambon
Jan 22, 1982·Nucleic Acids Research·S M Mount
Aug 13, 1993·Cell·A B Sachs
Jan 1, 1994·Advances in Pharmacology·C F Bennett, S T Crooke
Jul 25, 1993·Nucleic Acids Research·R BerganL Neckers
Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·Z Dominski, R Kole

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Citations

Dec 31, 1997·Biochemical Pharmacology·C F Bennett
May 7, 1998·European Journal of Pharmacology·P A Henricks, F P Nijkamp
Aug 24, 1999·Pharmacology & Therapeutics·S R CooperN M Dean
May 12, 2000·Biochimica Et Biophysica Acta·C F Bennett, L M Cowsert
May 12, 2000·Biochimica Et Biophysica Acta·B F Baker, B P Monia
May 12, 2000·Biochimica Et Biophysica Acta·D PraseuthC Hélène
May 4, 2001·Antisense & Nucleic Acid Drug Development·T P CondonC F Bennett
Aug 7, 2002·Antisense & Nucleic Acid Drug Development·C Frank Bennett
Apr 24, 2004·Oligonucleotides·Lingamanaidu V RavichandranEric G Marcusson
Aug 1, 1997·Antisense & Nucleic Acid Drug Development·C PichonA C Roche
Jan 25, 2000·Antisense & Nucleic Acid Drug Development·S H KangR Kole
May 22, 1998·Molecular Biology of the Cell·P LorenzD L Spector
Jan 31, 2002·Journal of Veterinary Internal Medicine·Z A RadiM R Ackermann
Jul 20, 2007·International Journal of Radiation Oncology, Biology, Physics·Satoshi AnaiCharles J Rosser
May 19, 2001·Clinical Immunology : the Official Journal of the Clinical Immunology Society·N A PatelS L Chang
Oct 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Clotilde Lagier-TourenneJohn Ravits
Jul 1, 2004·Organic & Biomolecular Chemistry·Hans Aström, Roger Strömberg
Jan 3, 2001·Nature Biotechnology·M FariaC Giovannangeli
Sep 19, 2017·Journal of Clinical Pharmacology·A Robert MacLeod, Stanley T Crooke
Sep 16, 2020·Pharmacological Reviews·Ai-Ming YuMei-Juan Tu
Dec 26, 2002·The Journal of Biological Chemistry·Timothy A VickersBrenda F Baker
Dec 1, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Junichi YanoTatsuro Irimura
Feb 22, 2001·Methods : a Companion to Methods in Enzymology·B F BakerB P Monia

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