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(Circulation Research. 1999;84:820-830.)
© 1999 American Heart Association, Inc.

Original Contribution

cdc25A Is Necessary but Not Sufficient for Optimal c-myc–Induced Apoptosis and Cell Proliferation of Vascular Smooth Muscle Cells

Kirsty Macdonald, Martin R. Bennett

From the Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

Correspondence to Martin R. Bennett, Department of Medicine, Box 157, Addenbrooke's Hospital, Cambridge CB22QQ, UK. E-mail mrb{at}mole.bio.cam.ac.uk

Abstract—Increasing evidence indicates that the control of cell proliferation and apoptosis are linked. The c-myc proto-oncogene is induced early after cell-cycle entry in vascular smooth muscle cells (VSMCs) in vitro and after arterial injury and regulates both cell proliferation and apoptosis. Although both proliferation and apoptosis are likely to be mediated via transcriptional activation of target genes, few c-myc targets have been identified. Therefore, the recent identification that cdc25A, a cell-cycle phosphatase involved in G₁ progression, is transcriptionally activated by c-myc and regulates c-myc–induced apoptosis has suggested that cdc25A may be the principal mediator of c-myc in VSMCs. We examined cdc25A regulation of c-myc–induced proliferation and apoptosis by expressing cdc25A or antisense cdc25A in primary rat VSMCs or in VSMCs expressing deregulated c-myc or adenovirus E1A. Ectopic c-myc increased cdc25A expression, but cdc25A was still responsive to serum components, which indicated that 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 G₁. Ectopic cdc25A augmented the proproliferative and proapoptotic action of c-myc but did not increase cell proliferation or apoptosis in the absence of ectopic 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 G₁. However, cdc25A alone does not induce apoptosis and cannot substitute for c-myc in VSMCs. Additional targets of c-myc are therefore involved in apoptosis of both G₁ and post-G₁ VSMCs.

Key Words: apoptosis • phosphatase • c-myc • adenovirus • vascular smooth muscle cell

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