THE PROTOONCOGENE BCL-3 ENCODES AN I-KAPPA-B PROTEIN

The bcl-3 gene product, overexpressed in chronic lymphocytic leukemia (CLL) patients with the translocation t(14;19), is a member of the IkappaB family. The bcl-3 protein is able to inhibit the DNA binding and trans-activation of authentic NF-kappaB heterodimers p50-p65 and p49-p65, as well as p50 and p49 homodimers. The bcl-3 protein does not inhibit either the DNA-binding activity of the Rel protein or its ability to trans-activate genes linked to the kappaB site. A human 37-kD protein (IkappaBalpha), identified previously as a member of the IkappaB family, is also unable to inhibit DNA-binding activity of the Rel protein. However, unlike bcl-3, the 37-kD (IkappaBalpha) protein has no effect on the DNA-binding activity of p50 or p49 homodimers. Two dimensional phosphotryptic peptide maps of the human bcl-3 and the human 37-kD (IkappaBalpha) proteins reveal that the phosphopeptides from the 37-kD (IkappaBalpha) protein are nested within the bcl-3 protein. Furthermore, bcl-3 antisera immunoprecipitates an in vitro-radiolabeled 37-kD (IkappaBalpha) protein. Proteins of 56 and 38 kD can be identified in HeLa cells stimulated with PMA and immunoprecipitated with bcl-3 antisera. Comparison of tryptic peptide maps of the bcl-3 protein synthesized in vitro, and p56 and p38 from HeLa cells, shows that they are all structurally related. Removal of the amino-terminal sequences of the bcl-3 protein generates a protein that inhibits the DNA binding of the p50-p65 heterodimer but, like the 37-kD (IkappaBalpha) protein, is no longer able to inhibit the binding of the p50 and p49 homodimers with kappaB DNA. We propose that the bcl-3 and 37-kD (IkappaBalpha) proteins are related and are members of the IkappaB family.