TY - JOUR
T1 - Sequence-independent induction of Sp1 transcription factor activity by phosphorothioate oligodeoxynucleotides
AU - Perez, Jose R.
AU - Li, Yuling
AU - Stein, C. A.
AU - Majumder, Sadhan
AU - Van Oorschot, Astrid
AU - Narayanan, Ramaswamy
PY - 1994/6/21
Y1 - 1994/6/21
N2 - 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-κB activity, since inhibition of NF-κB 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 nonspecific effects often seen with [S]ODNs.
AB - 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-κB activity, since inhibition of NF-κB 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 nonspecific effects often seen with [S]ODNs.
KW - NF-κB
KW - antisense therapy
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U2 - 10.1073/pnas.91.13.5957
DO - 10.1073/pnas.91.13.5957
M3 - Article
C2 - 8016096
AN - SCOPUS:0028340194
SN - 0027-8424
VL - 91
SP - 5957
EP - 5961
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -