Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal...

Members of the cdc25 family are protein phosphatases that play pivotal roles in cell cycle progression. Cdc25A has been shown to be a critical regulator of the G1/S transition of mammalian cells and to be a myc-target gene with oncongenic properties. We investigated the regulation of cdc25A during terminal differentiation using myeloblastic leukemia M1 cells, that can be induced to undergo differentiation into macrophages by interleukin-6 (IL-6) treatment. In this report it is shown that cdc25A protein is degraded by the ubiquitin-proteasome machinery in both terminally differentiating and cycling cells. Cdc25A was found to have two major peaks of accumulation during cell cycle progression, one in G1 and the other in S/G2. Evidence was obtained that degradation of cdc25A by the ubiquitin-proteasome machinery in terminally differentiating myeloid cells is accelerated compared to cycling cells. Moreover, deregulated expression of c-myc in M1 cells, which had been previously shown to block terminal differentiation, was also found to block IL-6 induced degradation of cdc25A.