p65

p65 most commonly refers to the 65-kilodalton subunit of the NF-κB transcription factor, encoded by the RELA gene in humans, also known as RelA. In humans, RELA is located on chromosome 11. NF-κB is a dimeric transcription factor that controls the expression of genes involved in immune and inflammatory responses. The p65/p50 heterodimer represents the canonical form that activates transcription of target genes upon stimulation.

Structure and domains: p65 contains a Rel homology domain responsible for DNA binding and dimerization, and a C-terminal transactivation domain that promotes transcriptional activation. It also has nuclear localization signals that regulate movement to the nucleus.

Regulation: In resting cells, NF-κB dimers are retained in the cytoplasm by IκB inhibitors. Stimulatory signals activate the IκB kinase (IKK) complex, leading to phosphorylation and degradation of IκB proteins. This releases p65/p50, enabling nuclear translocation and binding to κB motifs to drive gene expression.

Post-translational modifications: Phosphorylation (for example at Ser276 and Ser536), acetylation, ubiquitination, and sumoylation regulate transcriptional activity, DNA binding, subcellular localization, and interactions with coactivators.

Interaction and function: p65 interacts with coregulators such as CBP/p300 and BRD4, as well as other transcription factors, to modulate transcriptional outcomes. It participates in feedback loops that regulate inflammatory and stress responses.

Clinical and research relevance: Dysregulated p65 activity is associated with inflammatory diseases, autoimmune disorders, and cancer. Therapeutic strategies often target NF-κB signaling components, including IKK inhibitors and modulators of p65 activity.