Transcription factor decoy approach to decipher the role of NF-kappa B in oncogenesis.
Antisense inhibition of the RelA subunit of NF-kappa B transcription factor (but not the NFKB1 subunit) causes pronounced inhibition of tumor cell growth in vitro and in vivo. Inhibition of either subunit, however, results in inhibition of the heterodimeric NF-kappa B complex in antisense-treated cells. Either of the subunits of NF-kappa B can form homo- or heterodimers with other members of the Rel oncogene family. In an effort to decipher the role of homo- vs heterodimeric NNF-kappa B in regulating tumor cell growth, we have used a decoy approach to trap these complexes in vivo. Using double-stranded phosphorothioates as a direct in vivo competitor for homo- vs heterodimeric NF-kappa B, we demonstrate that decoys more specific to RelA inhibit growth tumor cell growth in vitro. We demonstrate that RelA, either as a homodimer or a heterodimer with some other members of the Rel family and not the classical NF-kappa B (RelA/NFKB1), is involved in the differential growth control of tumor cells. Our results indicate that such transcription factor decoys can be a non-antisense tool to study the function of DNA-binding transcription factors.
Sharma
H W
HW
Division of Oncology, Roche Research Center, Hoffman-La Roche Inc., Nutley, NJ 07110, USA.
Perez
J R
JR
Higgins-Sochaski
K
K
Hsiao
R
R
Narayanan
R
R
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism; D005354:Fibrosarcoma / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000235:genetics; D013873:Thionucleotides / Q000494:pharmacology*; D051996:Transcription Factor RelA
D004273:DNA, Neoplasm; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D016329:Sp1 Transcription Factor; D013873:Thionucleotides; D051996:Transcription Factor RelA