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(Circulation Research. 1997;80:617-626.)
© 1997 American Heart Association, Inc.

Articles

c-Myb–Dependent Cell Cycle Progression and Ca²⁺ Storage in Cultured Vascular Smooth Muscle Cells

Mansoor Husain, Kiflai Bein, Lianwei Jiang, Seth L. Alper, Michael Simons, , Robert D. Rosenberg

From the Department of Biology (M.H., R.D.R.), Massachusetts Institute of Technology; the Cardiovascular (M.H., K.B., M.S.) and Molecular Medicine (L.J., S.L.A., R.D.R.) Divisions, Beth Israel Hospital; and the Departments of Medicine and Cell Biology (S.L.A.), Harvard Medical School, Boston, Mass.

Correspondence to Robert D. Rosenberg, MD, PhD, Massachusetts Institute of Technology, Building 68, Room 480, 31 Ames St, Cambridge, MA 02139. E-mail rdrrosen{at}mit.edu

Abstract Considerable controversy surrounds the role of the c-myb proto-oncogene in vascular smooth muscle cells (VSMCs). Previous investigations using antisense approaches have suggested a relationship between c-myb expression, cell cycle progression, and cytoplasmic Ca²⁺ concentration ([Ca²⁺]_cyt). However, the ability of certain antisense oligonucleotides to bind and inactivate growth factors allows alternative explanations. To define more specifically the role of c-Myb in cultured VSMCs (SVE and A10 cell lines), we have generated stable cell clones expressing a dominant-negative c-Myb lacking critical elements of the DNA binding domain (5-SVE) and transiently transfected cell populations (GRE-MEn-SVE and GRE-MEn-A10) expressing a glucocorticoid-inducible chimeric protein that targets the Drosophila Engrailed repressor domain to c-Myb–responsive promoters. The 5-SVE clones and GRE-MEn cell populations exhibit a 60% reduction in mean intracellular c-Myb activity, as measured by cotransfection assays with a c-Myb–responsive reporter, a 42% decrease in the mean S phase entry of growth-arrested (G₀) cells after serum stimulation, and a 36% inhibition of mean cell proliferation over 4 days. These cells also display 28% (34-nmol/L) and 30% (42-nmol/L) reductions in mean [Ca²⁺]_cyt at G₀ and at the G₁/S interface, respectively, as well as significant reductions in the peak [Ca²⁺]_cyt responses to thapsigargin (5 µmol/L) and caffeine (10 mmol/L). These latter reductions in operationally defined Ca²⁺ pools were observed both at different stages of the cell cycle and after transient induction of the dominant-interfering construct, suggesting that c-Myb regulates these releasable Ca²⁺ stores independent of its effects on cell cycle progression.

Key Words: cell cycle • Ca²⁺ • oncogene

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