BCR-ABL prevents c-Jun-mediated and proteasome-dependent FUS (TLS) proteolysis through a protein kinase C beta II-dependent pathway

The DNA binding activity of FUS (also known as TLS), a nuclear pro-oncogene involved in multiple translocations, is regulated by BCR-ABL in a protein kinase cpn (PKC beta II)-dependent manner. We show here that in normal myel oid progenitor cells FUS, although not visibly ubiquitinated, undergoes pro teasome-dependent degradation, whereas in BCR-ABL-expressing cells, degrada tion is suppressed by PKC beta II phosphorylation. Replacement of serine 25 6 with the phosphomimetic aspartic acid prevents proteasome-dependent prote olysis of FUS, while the serine-256-to-alanine FUS mutant is unstable and s usceptible to degradation. Ectopic expression of the phosphomimetic S256D F US mutant in granulocyte colony-stimulating factor-treated 32Dcl3 cells ind uces massive apoptosis and inhibits the differentiation of the cells escapi ng cell death, while the degradation-prone S256A mutant has no effect on ei ther survival or differentiation. FUS proteolysis is induced by c-Jun, is s uppressed by BCR-ABL or Jun kinase 1, and does not depend on c-Jun transact ivation potential, ubiquitination, or its interaction with Jun kinase 1, In addition, c-Jun induced FUS proteasome-dependent degradation is enhanced b y heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and depends on the for mation of a FUS-Jun-hnRNP A1-containing complex and on lack of PKC beta II phosphorylation at serine 256 but not on FUS ubiquitination. Thus, novel me chanisms appear to be involved in the degradation of FUS in normal myeloid cells; moreover, the ability of the BCR-ABL oncoprotein to suppress FUS deg radation by the induction of posttranslational modifications might contribu te to the phenotype of BCR-ABL expressing hematopoietic cells.