Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor
Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor
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DOI：
10.1002/mc.10106
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发表时间：
2003-03-01
影响因子：
4.6
通讯作者：
Djakiew, D
中科院分区：
文献类型：
--
作者：
Khwaja, F;Djakiew, D
神经营养因子（NTR）受体（p75（NTR））是与生长因子的神经营养因子家族结合的细胞表面糖蛋白，其原型成员是神经生长因子（NGF）。该受体先前显示通过诱导G期细胞的积累而延迟细胞周期进程，伴随着细胞周期S期细胞的减少。此外，p75（NTR）被证明是一个有效的肿瘤抑制膀胱癌细胞的生长在体内。为了研究p75（NTR）依赖性抑制细胞周期进程的机制，我们利用表达p75（NTR）的膀胱肿瘤细胞的转基因克隆，以增加浓度来证明p75（NTR）对调节肿瘤细胞增殖的细胞周期调节蛋白水平的影响。p75（NTR）蛋白表达的等级顺序（剂量依赖性）增加与细胞增殖减少相关。这种p75（NTR）依赖性的增殖抑制用NGF拯救。在没有配体的情况下，p75（NTR）蛋白表达的剂量依赖性增加与细胞周期蛋白D1、细胞周期蛋白E和细胞周期蛋白依赖性激酶2（cdk 2）的表达减少以及cdk 2活性降低相关。过度磷酸化的视网膜母细胞瘤蛋白、转录因子E2 F1和增殖细胞核抗原的表达也减少，而低磷酸化的Rb和cdk抑制剂p16（Ink 4a）的表达增加，p75（NTR）的表达增加。用NGF治疗肿瘤细胞改善了这些p75（NTR）依赖的细胞周期调节蛋白水平的变化，并从p75（NTR）依赖的增殖抑制中拯救了肿瘤细胞。因此，可以得出结论，p75（NTR）通过改变细胞周期调节蛋白的表达来抑制增殖，并且NGF改善了这种效果。(C)2003 Wiley-Liss，Inc.
The neurotrophin (NTR) receptor (p75(NTR)) is a cell-surface glycoprotein that binds to the neurotrophin family of growth factors, of which the prototypic member is nerve growth factor (NGF). This receptor was previously shown to retard cell-cycle progression by inducing accumulation of cells in G, with a concomitant reduction of cells in the S phase of the cell cycle. Furthermore, p75(NTR) was shown to be an effective tumor suppressor of bladder cancer cell growth in vivo. In order to investigate the mechanism of p75(NTR)-dependent suppression of cell-cycle progression, we utilized transgenic clones of bladder tumor cells that express p75(NTR) in increasing concentrations to demonstrate an effect of p75(NTR) on the levels of cell-cycle regulatory proteins that modulate proliferation of tumor cells. A rank-order (dose-dependent) increase in p75(NTR) protein expression was associated with a decrease in cell proliferation. This p75(NTR)-dependent suppression of proliferation was rescued with NGF. In the absence of ligand, a dose-dependent increase in p75(NTR) protein expression was associated with reduced expression of cyclin D1, cyclin E, and cyclin-dependent kinase 2 (cdk2) as well as decreased cdk2 activity. There was also a decrease in the expression of hyperphosphorylated retinoblastoma protein, the transcription factor E2F1, and proliferating cell nuclear antigen, and there was an increase in expression of hypophosphorylated Rb and the cdk inhibitor p16(Ink4a), with increasing p75(NTR) expression. Treatment of tumor cells with NGF ameliorated these p75(NTR)-dependent changes in the levels of cell-cycle regulatory proteins and rescued the tumor cells from p75(NTR)-dependent inhibition of proliferation. Hence, it can be concluded that p75(NTR) inhibits proliferation by altering the expression of cell-cycle regulatory proteins and that NGF ameliorates this effect. (C) 2003 Wiley-Liss, Inc.