Disruption of I kappa B alpha regulation by antisense RNA expression leads to malignant transformation.

Abstract

NF-kappa B transcription factors regulate the expression of a variety of genes involved in immune regulation and cell growth. In most cell types NF-kappa B proteins are localized in an inactive form in the cytoplasm coupled to the inhibitory I kappa B proteins. Viruses, cytokines, lipopolysaccharides and other stimulating agents promote the dissociation of the cytosolic NF-kappa B/I kappa B complexes, via phosphorylation and degradation of I kappa B, resulting in the translocation of DNA binding, NF-kappa B complexes to the nucleus. To further understand the association of I kappa B with cell growth regulation, the effect of ectopic expression of sense and antisense I kappa B genes was examined in NIH3T3 cells. Overexpression of I kappa B alpha antisense RNA but not I kappa B gamma antisense RNA decreased the steady state levels of I kappa B alpha protein, altered NF-kappa B DNA binding and gene activity and, most importantly, induced malignant transformation as measured by saturation density, growth in soft agar and tumorigenicity in nude mice. In contrast, overexpression of I kappa B alpha resulted in decreased saturation density, a flattened cellular morphology and decreased NF-kappa B dependent reporter gene activity. These results indicate that overexpression of an I kappa B alpha antisense RNA may disrupt the NF-kappa B/I kappa B autoregulatory loop, leading to cellular transformation. Our results raise the interesting possibility that I kappa B alpha represents a potential tumor suppressor activity.

• Authors: P Beauparlant, I Kwan, R Bitar, P Chou, A E Koromilas, N Sonenberg, J Hiscott
• Journal: Oncogene (Oncogene) Vol. 9 Issue 11 Pg. 3189-97 (Nov 1994) ISSN: 0950-9232 [Print] England
• PMID: 7936641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• I-kappa B Proteins
• NF-kappa B
• NF-kappa B p50 Subunit
• NFKB1 protein, human
• NFKBIA protein, human
• Nfkbia protein, mouse
• Oligodeoxyribonucleotides
• RNA, Antisense
• Transcription Factors
• NF-KappaB Inhibitor alpha
• Nfkb1 protein, mouse

Topics

• 3T3 Cells
• Animals
• Base Sequence
• Cell Transformation, Neoplastic
• Clone Cells (metabolism)
• DNA-Binding Proteins (genetics)
• Gene Expression
• Humans
• I-kappa B Proteins
• Mice
• Mice, Nude
• Molecular Sequence Data
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, physiology)
• NF-kappa B p50 Subunit
• Oligodeoxyribonucleotides
• Protein Binding
• RNA, Antisense (biosynthesis, genetics)
• Transcription Factors (genetics)