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(Circulation Research. 2000;86:68.)
© 2000 American Heart Association, Inc.

Cellular Biology

Differentiation-Inducing Factor-1, a Morphogen of Dictyostelium, Induces G₁ Arrest and Differentiation of Vascular Smooth Muscle Cells

Yoshikazu Miwa, Toshiyuki Sasaguri, Chiya Kosaka, Yoji Taba, Akio Ishida, Takeo Abumiya, Yuzuru Kubohara

From the Departments of Bioscience (Y.M., T.S., Y.T., A.I.) and Epidemiology (T.A.), National Cardiovascular Center Research Institute; Second Department of Internal Medicine, Faculty of Medicine, Kyushu University (Y.M.); Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University (C.K.); and Department of Molecular Physiology, Institute for Molecular and Cellular Regulation, Gunma University (Y.K.), Japan.

Correspondence to Toshiyuki Sasaguri, MD, PhD, Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail sasaguri{at}ri.ncvc.go.jp

Abstract—Differentiation-inducing factor-1 (DIF-1) is a morphogen that induces differentiation of Dictyostelium. Recently, DIF-1 has been shown to inhibit proliferation and induce differentiation in tumor cells, although the underlying mechanisms remain unknown. In this study, we examined the effects of DIF-1 on the proliferation and differentiation of vascular smooth muscle cells, to explore novel therapeutic strategies for atherosclerosis. DIF-1 nearly completely inhibited DNA synthesis and cell division in mitogen-stimulated cells. DIF-1 inhibited the phosphorylation of the retinoblastoma protein and the activities of cyclin-dependent kinase (Cdk) 4, Cdk6, and Cdk2, which phosphorylate the retinoblastoma protein. DIF-1 strongly suppressed the expression of cyclins D1, D2, and D3, as well as those of cyclins E and A, which normally began after that of the D-type cyclins. The mRNAs for the smooth muscle myosin heavy chains SM1 and SM2 were expressed in quiescent cells in primary culture, and these expression levels decreased after mitogenic stimulation. In the presence of DIF-1, the rate of the reduction was significantly decelerated. Moreover, the addition of DIF-1 to dedifferentiated cells induced the expressions of SM1 and SM2, accompanied by a reduction in the level of SMemb, a nonmuscle-type myosin heavy chain. Therefore, DIF-1 seemed to interrupt a very early stage of G₁ probably by suppressing the expressions of the D-type cyclins. Furthermore, this compound may prevent phenotypic modulation and induce differentiation of vascular smooth muscle cells.

Key Words: differentiation-inducing factor-1 • vascular smooth muscle cell • cell cycle • cyclin • differentiation

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