ENHANCED I-KAPPA-B-ALPHA DEGRADATION IS RESPONSIBLE FOR CONSTITUTIVE NF-KAPPA-B ACTIVITY IN MATURE MURINE B-CELL LINES

Nuclear factor kappa B (NF-kappa B) is a ubiquitous transcription fact or which binds to decameric DNA sequences (kappa B sites) and regulate s transcription of multiple genes. The activity of NF-kappa B is regul ated by an inhibitor protein, I kappa B, which sequesters NF-kappa B i n the cytoplasm. Release of I kappa B and subsequent nuclear transloca tion of NF-kappa B generally require activating signals. However, in m ature murine B cells, the DNA-binding activity of NF-kappa B is consti tutively nuclear and activates the Ig kappa gene, a marker for mature B cells. To understand the basis for the constitutive NF-kappa B activ ation, we examined the properties of NF-kappa B and I kappa B in both pre-B and mature B cells, the regulated and constitutive states, respe ctively. We found that expression of I kappa B alpha and p105, members of the I kappa B family, and Rel, a member of the NF-kappa B family, is augmented in mature B cells. Both I kappa B alpha and p105 are asso ciated with NF-kappa B proteins and sequester most of these proteins i n the cytoplasm of mature B cells. However, rapid I kappa B alpha diss ociation and degradation lead to continuous nuclear translocation of a small fraction of NF-kappa B proteins, which represent the constituti vely active NF-kappa B in mature B cells. We estimate that the proteas e activity is at least 35-fold greater in mature B cells than in pre-B cells. Rapid degradation of I kappa B alpha is directly involved in c onstitutive NF-kappa B activation, because stabilization of I kappa B alpha by a protease inhibitor causes loss of NF-kappa B activity in ma ture B cells. These results provide evidence that continuous and rapid degradation of I kappa B alpha in the absence of external stimuli is causally involved in the constitutive activation of NF-kappa B in matu re murine B cells.