The p65 subunit of NF-κB regulates IκB by two distinct mechanisms

Transcription factor NF-κB (p50/p65) is generally localized to the cytoplasm by its inhibitor IκB. Overproduced IκB, free from NF-κB, is rapidly degraded. Overexpression of p65 increases endogenous IκB protein in both carcinoma and lymphoid cells by two mechanisms: protein stabilization and increased transcription of IκB mRNA. In contrast, p65Δ, a naturally occurring splice variant, fails to markedly augment IκB protein levels. Both overexpressed p65 and coexpressed p50 are cytoplasmic, whereas p65Δ is partly nuclear, indicating that the IκB induced by p65 can maintain NF-κB in the cytoplasm. Thus, p65 and IκB are linked in an autoregulatory loop, ensuring that NF-κB is held in the cytoplasm until cells are specifically induced to translocate it to the nucleus.