Differentiation-inducing factor-1, a morphogen of Dictyostelium, induces G1 arrest and differentiation of vascular smooth muscle cells

被引:44
作者
Miwa, Y
Sasaguri, T
Kosaka, C
Taba, Y
Ishida, A
Abumiya, T
Kubohara, Y
机构
[1] Natl Cardiovasc Ctr, Inst Res, Dept Biosci, Suita, Osaka 5658565, Japan
[2] Natl Cardiovasc Ctr, Inst Res, Dept Epidemiol, Suita, Osaka 5658565, Japan
[3] Kyushu Univ, Fac Med, Dept Internal Med 2, Fukuoka 812, Japan
[4] Kansai Med Univ, Dept Clin Sci & Lab Med, Moriguchi, Osaka, Japan
[5] Gunma Univ, Inst Mol & Cellular Regulat, Dept Mol Physiol, Gunma, Japan
关键词
differentiation-inducing factor-1; vascular smooth muscle cell; cell cycle; cyclin; differentiation;
D O I
10.1161/01.RES.86.1.68
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
-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 G(1), 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.
引用
收藏
页码:68 / 75
页数:8
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