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Antisense rel A in Cancer
J R Perez1, K A Higgins-Sochaski, J Y Maltese
1Division of Oncology, Roche Research Center, Hoffmann-La Roche, Nutley, NJ.
Abstract:
NFKB: is a pleiotropic transcription factor that participates in the induction of various cellular and viral genes (for a review, see refs. 1 and 2). The principal form of this active complex is composed of two polypeptides, p65 (recently renamed rel A) and p50 (recently renamed NFKB1) (3, 4). Both of these sub-units belong to the rel famtly of transcription factors with homology in the amino terminus (5, 6). Since the original identification of these factors, several others have been identified in this family of transcription factors: P49, c-rel, p100, rel B, dorsal, Bcl-3, and p105 (1). The NF-kheterodimer is associated in the cytoplasm with the IkB subunit, which sequesters this factor in an inactive state (7). On activation by various stimuli, the IkB subunit separates from the active NFheterodimer, and the active complex is translocated to the nucleus where it binds to its nuclear DNA target sequence (Fig. 1). The principal cause for disassociation of IkB from NFis phosphorylation (8), but it may involve proteolysis of IkB (9) Several autoregulatory loops have been proposed for the involvement of NF-kB in the regulation of the inhibitor IkB. Furthermore, NF-kB has been shown to regulate the transcription of IkB and NFKB1 (10-12). Fig. 1. NF-K: B transcription factor. This figure depicts the basis for the function of the NF-K: B transcription factor. The principal form of the NF-K: B transcription complex is as a heterodimer composed of the two subunits: rel A and NF-K: B 1. The inactive complex is sequestered in the cytoplasm associated with the inhibitor protein, IK: B. On activation, the IK: B protein separates from the active complex through a mechanism involving the phosphorylation and proteolysis Of IK: B. The active NF-K: B complex is then translocated to the nucleus where it binds DNA in a sequence-specific manner and interacts with the transcriptional machinery to modulate the rate of transcription of target genes.
Insights
Nuclear Factor kappa B (NF-κB) is a transcription factor regulating cellular and viral genes. Upon activation, it translocates to the nucleus to control gene transcription.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- Nuclear Factor kappa B (NF-κB) is a pleiotropic transcription factor involved in regulating cellular and viral genes.
- The active NF-κB complex is a heterodimer of p65 (rel A) and p50 (NFKB1) subunits, belonging to the rel family of transcription factors.
- NF-κB is held inactive in the cytoplasm by the inhibitor of NF-κB (IκB) subunit.
Purpose of the Study:
- To elucidate the mechanism of NF-κB activation and its role in gene regulation.
- To describe the structural components and activation pathway of the NF-κB transcription factor.
Main Methods:
- Review of existing literature and experimental findings on NF-κB.
- Analysis of the protein subunits (p65/rel A, p50/NFKB1) and their interactions.
- Description of the regulatory role of IκB and its dissociation mechanism.
Main Results:
- NF-κB activation involves the dissociation of IκB from the NF-κB heterodimer.
- This dissociation is triggered by stimuli leading to IκB phosphorylation and/or proteolysis.
- The active NF-κB complex translocates to the nucleus to bind DNA and modulate target gene transcription.
Conclusions:
- NF-κB plays a critical role in gene expression, with its activity tightly regulated by IκB.
- The phosphorylation and proteolysis of IκB are key events in NF-κB pathway activation.
- NF-κB is involved in autoregulatory loops controlling IκB and NFKB1 gene transcription.
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