Cdc25A is necessary but not sufficient for optimal c-myc-induced apoptosisand cell proliferation of vascular smooth muscle cells

Increasing evidence indicates that the control of cell proliferation and ap optosis are linked. The c-myc proto-oncogene is induced early after cell-cy cle entry in vascular smooth muscle cells (VSMCs) in vitro and after arteri al injury and regulates both cell proliferation and apoptosis. Although bot h proliferation and apoptosis are likely to be mediated via transcriptional activation of target genes, few c-myc targets have been identified. Theref ore, the recent identification that cdc25A, a cell-cycle phosphatase involv ed in G(1) progression, is transcriptionally activated by c-myc and regulat es c-myc-induced apoptosis has suggested that cdc25A may be the principal m ediator of c-myc in VSMCs. We examined cdc25A regulation of c-myc-induced p roliferation and apoptosis by expressing cdc25A or antisense dcd25A express ion, but cdc25A was still responsive to serum components, which indicated t hat c-myc alone is not the main determinant of cdc25A expression. Antisense cdc25A inhibited c-myc-induced proliferation and apoptosis; however, drug and metabolic blocks indicated that this effect was limited to G(1). Ectopi c cdc25A augmented the proproliferative and proapoptotic action of c-myc bu t did not increase cell proliferation or apoptosis in the absence of ectopi c c-myc. In contrast, E1A/E2F-induced apoptosis was independent of cdc25A. We conclude that cdc25A expression modulates the ability of c-myc to induce apoptosis in G(1). However, cdc25A alone does not induce apoptosis and can not substitute for c-myc in VSMCs. Additional targets of c-myc are therefor e involved in apoptosis of both G(1) and post-G(1) VSMCs.