UBIQUITIN-DEPENDENT DEGRADATION OF CYCLIN-B IS ACCELERATED IN POLYPLOID MEGAKARYOCYTES

During the endomitotic cell cycle of megakaryocytic cell lines, the le vels of cyclin B1 and the activity of cyclin B1-dependent Cdc2 kinase, although detectable, are reduced as compared with megakaryocytes unde rgoing a mitotic cell cycle, The levels of cyclin A, however, are comp arable during both cell cycles, The expression of cyclin B1 mRNA is al so equivalent in proliferating and polyploidizing cells, In the curren t study, we found that the rate of cyclin B1 protein degradation is en hanced in polyploidizing megakaryocytes, This finding has led us to fu rther investigate whether the ubiquitin-proteosome pathway responsible for cyclin B degradation is accelerated in these cells, Our data indi cate that polyploidizing megakaryocytic cell lines and primary bone ma rrow cells treated with the megakaryocyte proliferation-and ploidy-pro moting factor, the c-Mpl ligand, display increased activities of the u biquitin-proteosome pathway, which degrades cyclin B, as compared with proliferating megakaryocytic cell lines or diploid bone marrow cells, respectively. This degradation has all the hallmarks of a ubiquitin p athway, including the dependence on ATP, the appearance of high molecu lar weight conjugated forms of cyclin B, and inhibition of the proteol ytic process by a mutated form of the ubiquitin-conjugating enzyme Ubc 4., Our studies also indicate that the ability to degrade cyclin A is equivalent in both the mitotic and endomitotic cell cycles, The increa sed potential of polyploid megakaryocytes to degrade cyclin B may be p art of the cellular programming that leads to aborted mitosis.