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Transcription factor decoy approach to decipher the role of NF-kappa B in oncogenesis
H W Sharma1, J R Perez, K Higgins-Sochaski
1Division of Oncology, Roche Research Center, Hoffman-La Roche Inc., Nutley, NJ 07110, USA.
Abstract:
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.
Insights
Targeting the RelA subunit of the NF-kappa B (Nuclear Factor kappa-light-chain-enhancer of activated B cells) transcription factor inhibits tumor cell growth. Specific decoys targeting RelA show promise as a non-antisense tool for studying transcription factor function.
Area of Science:
- Molecular biology
- Cancer research
- Transcription factor regulation
Background:
- Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) is a transcription factor complex involved in cell growth.
- NF-kappa B consists of subunits, including RelA and NFKB1, which can form homo- and heterodimers.
- The specific roles of different NF-kappa B dimer formations in tumor cell growth are not fully understood.
Purpose of the Study:
- To investigate the role of RelA homo- and heterodimers in regulating tumor cell growth.
- To explore the potential of transcription factor decoys as a tool to study NF-kappa B function.
- To differentiate the function of RelA-containing dimers from the classical NF-kappa B (RelA/NFKB1) complex.
Main Methods:
- Utilized antisense inhibition targeting RelA and NFKB1 subunits of NF-kappa B.
- Employed a decoy approach using double-stranded phosphorothioates as in vivo competitors for NF-kappa B complexes.
- Assessed tumor cell growth inhibition in vitro and in vivo.
Main Results:
- Antisense inhibition of RelA, but not NFKB1, significantly inhibited tumor cell growth.
- Decoys specific to RelA demonstrated pronounced inhibition of tumor cell growth in vitro.
- RelA, in various homo- and heterodimeric forms (excluding classical NF-kappa B), plays a critical role in differential tumor cell growth control.
Conclusions:
- RelA-containing NF-kappa B complexes are key regulators of tumor cell proliferation.
- Transcription factor decoys offer a novel, non-antisense strategy for investigating DNA-binding transcription factor functions.
- Targeting RelA-specific dimers presents a potential therapeutic avenue for cancer treatment.