Nuclear beta-catenin displays GSK-3 beta- and APC-independent proteasome sensitivity in melanoma cells

Colon carcinoma and melanoma cells containing either a deletion of the aden omatous polyposis coli tumor suppressor protein (APC) or mutation of the si te in beta-catenin phosphorylated by glycogen synthase kinase-3 beta (GSK-3 beta) display elevated levels of detergent-soluble beta-catenin due to ins ensitivity of the cytosolic protein to proteasome-dependent degradation. In this study, we have examined the effect of beta-catenin mutation (S37F) or APC loss on the proteasome sensitivity of additional subcellular beta-cate nin pools in melanoma cells. In contrast to detergent-soluble beta-catenin, the detergent-insoluble protein remains proteasome-sensitive irrespective of S37F mutation or APC status. This insoluble component appears associated primarily with nuclear cytoskeletal elements. In addition, DNase I treatme nt solubilized a portion of detergent-insoluble beta-catenin, suggesting th at this fraction also contains chromatin-associated protein, and correlatin g with a proteasome-sensitive elevation in beta-catenin-stimulated reporter activity. Since the detergent-insoluble nuclear component of beta-catenin displays GSK-3 beta- and APC-indepcndent proteasome sensitivity, distinct f rom the soluble nuclear and cytosolic pools of this protein, regulation of beta-catenin proteasome sensitivity and the contribution of this process to beta-catenin function may be more complex than previously appreciated. (C) 2000 Elsevier Science B.V. All rights reserved.