THE P65-SUBUNIT OF NF-KAPPA-B REGULATES I-KAPPA-B BY 2 DISTINCT MECHANISMS

Transcription factor NF-kappaB (p50/p65) is generally localized to the cytoplasm by its inhibitor IkappaB. overproduced IkappaB, free from NF-kappaB, is rapidly degraded. Overexpression of p65 increases endogenous IkappaB protein in both carcinoma and lymphoid cells by two mechanisms: protein stabilization and increased transcription of IkappaB mRNA. In contrast, p65DELTA, a naturally occurring splice variant, fails to markedly augment IkappaB protein levels. Both overexpressed p65 and coexpressed p50 are cytoplasmic, whereas p65DELTA is partly nuclear, indicating that the IkappaB induced by p65 can maintain NF-kappaB in the cytoplasm. Thus, p65 and IkappaB are linked in an autoregulatory loop, ensuring that NF-kappaB is held in the cytoplasm until cells are specifically induced to translocate it to the nucleus.