Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes

被引:106
作者
Nelsen, CJ
Rickheim, DG
Tucker, MM
Hansen, LK
Albrecht, JH
机构
[1] Hennepin Cty Med Ctr, Dept Med 865B, Minneapolis, MN 55415 USA
[2] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
[3] Minneapolis Med Res Fdn Inc, Minneapolis, MN 55404 USA
关键词
D O I
10.1074/jbc.M209374200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Signaling through the target of rapamycin is required for increased protein synthesis, cell growth, and proliferation in response to growth factors. However, the downstream mediators of these responses, and the elements linking growth and proliferation, have not been fully elucidated. Rapamycin inhibits hepatocyte proliferation in culture and liver regeneration in vivo. In cultured rat hepatocytes, rapamycin prevented the up-regulation of cyclin D1 as well as proteins acting downstream in the cell cycle. Transfection with cyclin D1 or E2F2, but not cyclin E or activated Akt, overcame the rapamycin-mediated cell cycle arrest. Rapamycin also inhibited the induction of global protein synthesis after growth factor stimulation, and cyclin D1 overcame this inhibition. Rapamycin inhibited hepatocyte proliferation and cyclin D1 expression in the mouse liver after 70% partial hepatectomy. In rapamycin-treated mice, transfection with cyclin D1 induced hepatocyte proliferation, increased hepatocyte cell size, and promoted growth of the liver. These results suggest that cyclin D1 is a key mediator of increased protein synthesis, cell growth, and proliferation downstream of target of rapamycin in mitogen-stimulated hepatocytes.
引用
收藏
页码:3656 / 3663
页数:8
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