ALPHA-INTERFERON SUPPRESSES THE CYCLIN D3 AND CDC25A GENES, LEADING TO A REVERSIBLE G(0)-LIKE ARREST

Alpha interferon is a potent growth inhibitor of Daudi Burkitt's lymph oma cells. We show here that alpha-interferon signaling interacted sim ultaneously with several components of the basic cell cycle machinery, causing cells to enter into a state that had many features characteri stic of the G(0) state. Within a few hours after alpha-interferon trea tment, cyclin D3 mRNA and protein levels dropped to undetectable level s and, in parallel, the activities of cyclin A- and cyclin E-associate d kinases were significantly reduced. The latter resulted from the rap id alpha-interferon-mediated elimination of cdc25A, a phosphatase that is required for antagonism of negative tyrosine phosphorylation of cd k2 in cyclin-cdk complexes, This regulation represents a novel mechani sm through which an external inhibitory cytokine interacts with the ce ll cycle machinery, At later time points after alpha-interferon treatm ent, the levels of the 55-kDa slowly migrating hyperphosphorylated for m of cyclin E and of cyclin A were also reduced, The antiproliferative effects were reversible, and cultures from which alpha interferon was removed reentered S phase after a lag that typically corresponded to approximately two doubling times, During this lag period, the expressi on of cyclin D3 and cyclin A, as well as of the cdc25A phosphatase, co ntinued to be switched off, in spite of the removal of alpha interfero n from the cell surface, In contrast, c-myc, which represents another downstream target gene that is subjected to negative regulation by alp ha interferon, was relieved from suppression much earlier, concomitant with the decay in early signaling of the cytokine, The delayed patter n of cyclin reexpression provides evidence that alpha-interferon signa ling imposes a G(0)-like state on this system.