Sequence-independent induction of Sp1 transcription factor activity by phosphorothioate oligodeoxynucleotides.
Modified analogues of antisense oligodeoxynucleotides (ODNs), particularly phosphorothioates ([S]ODNs), have been extensively used to inhibit gene expression. The potential sequence specificity of antisense oligomers makes them attractive as molecular drugs for human diseases. The use of antisense [S]ODNs to inhibit gene expression has been complicated by frequent nonspecific effects. In this study we show in diverse cell types that [S]ODNs, independent of their base sequence, mediated the induction of an Sp1 nuclear transcription factor. The [S]ODN-mediated Sp1 induction was rapid and was associated with elevated levels of Sp1 protein. This induction was dependent on NF-kappa B activity, since inhibition of NF-kappa B activity abolished the [S]ODN-induced Sp1 activity. [S]ODN-induced Sp1 activity was seen in mouse spleen cells following in vivo administration. Sp1 activity induced by [S]ODNs required the tyrosine kinase pathway and did not have transactivating potential. These results may help to explain some of the non-specific effects often seen with [S]ODNs.
Division of Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110.
J R
JR
Perez
Y
Y
Li
C A
CA
Stein
S
S
Majumder
A
A
van Oorschot
R
R
Narayanan
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics; D015345:Oligonucleotide Probes; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013873:Thionucleotides; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D015345:Oligonucleotide Probes; D016376:Oligonucleotides, Antisense; D016329:Sp1 Transcription Factor; D013873:Thionucleotides; D051996:Transcription Factor RelA