Nuclear factor kappa B RelA-containing transcriptional complex (NF-κB RelA)

Nuclear factor kappa B (NF-κB) RelA-containing transcriptional complexes, most notably the p65/p50 heterodimer, are master regulators of the canonical NF-κB signaling pathway (1.1.1). These complexes are typically sequestered in the cytoplasm by inhibitory IκB proteins; upon stimulation by pro-inflammatory cytokines or pathogens, the IκB kinase (IKK) complex phosphorylates IκB, leading to its proteasomal degradation and the subsequent nuclear translocation of the RelA complex (1.3.1). In the nucleus, RelA binds to specific DNA sequences to activate the transcription of genes involved in immune responses, inflammation, and cell survival (1.4.1). Dysregulation and constitutive activation of these complexes are key drivers in various malignancies, such as diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), as well as chronic inflammatory conditions like rheumatoid arthritis (1.2.1, 1.1.4). Therapeutic strategies targeting these complexes include IKK inhibitors, proteasome inhibitors, and novel selective degraders like PROTACs, although systemic inhibition carries significant risks of immunosuppression and hepatotoxicity (1.1.2, 1.3.3).

Other names

p65RelANFKB3Transcription factor p65NF-κB p50/p65 heterodimerNuclear factor NF-kappa-B p65 subunit

Drugs targeting these complexes primarily act by inhibiting the IκB kinase (IKK) complex to prevent IκB phosphorylation, inhibiting the proteasome to prevent IκB degradation, directly blocking p65 DNA binding or nuclear translocation, or utilizing proteolysis-targeting chimeras (PROTACs) for selective protein degradation.