RAPAMYCIN-FKBP INHIBITS CELL-CYCLE REGULATORS OF PROLIFERATION IN VASCULAR SMOOTH-MUSCLE CELLS
RAPAMYCIN-FKBP INHIBITS CELL-CYCLE REGULATORS OF PROLIFERATION IN VASCULAR SMOOTH-MUSCLE CELLS
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DOI：
10.1161/01.res.76.3.412
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发表时间：
1995-03-01
影响因子：
20.1
通讯作者：
MARKS, AR
中科院分区：
文献类型：
--
作者：
MARX, SO;JAYARAMAN, T;MARKS, AR
多种生长因子可以刺激静止的血管平滑肌细胞退出G0并重新进入细胞周期。大环内酯类抗生素雷帕霉素与其胞质受体 FKBP 结合，是一种免疫抑制剂和细胞增殖的有效抑制剂。在本研究中，检查了雷帕霉素对人和大鼠血管平滑肌细胞的抗增殖作用，并与相关免疫抑制剂 FK520 的作用进行了比较。在血管平滑肌细胞中，浓度低至 1 ng/mL 的雷帕霉素可抑制 DNA 合成和细胞生长。 FK520 是免疫抑制剂 FK506 的类似物，其结构与雷帕霉素相关，并与 FKBP 结合，但不抑制血管平滑肌细胞生长。摩尔过量的 FK520 阻断了雷帕霉素的抗增殖作用，表明雷帕霉素的作用需要与 FKBP 结合。 Rapamycin-FKBP 抑制 G1/S 期视网膜母细胞瘤蛋白磷酸化。这种对视网膜母细胞瘤蛋白磷酸化的抑制与 p33(cdk2) 激酶活性的降低有关。这些观察结果表明，雷帕霉素（而非 FK520）通过降低细胞周期激酶活性来抑制血管平滑肌细胞增殖。
Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33(cdk2) kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.