The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death
The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death
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DOI：
10.1038/sj.onc.1202910
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发表时间：
1999-09-16
期刊：
影响因子：
8
通讯作者：
Knudsen, ES
中科院分区：
文献类型：
--
作者：
Knudsen, KE;Weber, E;Knudsen, ES
目的在于检测视网膜母细胞瘤肿瘤抑制蛋白RE的精确功能的研究已经受到在大多数细胞类型中发生的异位表达的RE的快速磷酸化和失活的阻碍。因此，异位表达的RE是细胞增殖的不良抑制剂。我们设计了组成型活性RE蛋白PSM-RB，其不能通过磷酸化失活。使用这些蛋白，我们表明，与野生型RE不同，PSM-RB蛋白抑制多种肿瘤细胞类型的细胞周期进展。此外，与p16（ink 4a）不同，PSM-RB也是RB缺陷肿瘤细胞中细胞周期进展的有效抑制剂。令人惊讶的是，我们鉴定了对PSM-RB的细胞周期抑制作用具有抗性的肿瘤细胞系。这一发现挑战了RE必须在所有细胞中失活才能发生细胞周期进展的假设。这种“耐药”肿瘤系的进一步表征揭示了这些细胞的增殖仍然受到PSM-RB的抑制。我们表明，这是由于PSM-RB诱导的细胞死亡。因此，这些研究首次表明RE通过至少两种不同的机制抑制细胞增殖-抑制细胞周期进程和诱导细胞死亡。
Studies aimed at examining the precise function(s) of the retinoblastoma tumor suppressor protein, RE, have been hindered by the rapid phosphorylation and inactivation of ectopically expressed RE which occurs in the majority of cell types, Therefore, ectopically expressed RE is a poor inhibitor of cellular proliferation, We have designed constitutively active RE proteins, PSM-RB, that cannot be inactivated by phosphorylation, Using these proteins, we show that unlike wild-type RE, PSM-RB proteins inhibit cell cycle progression in a broad range of tumor cell types. Furthermore, unlike p16(ink4a), PSM-RB is also a potent inhibitor of cell cycle progression in RB-deficient tumor cells. Surprisingly, we identified a tumor cell line that is resistant to the cell cycle inhibitory effects of PSM-RB. This finding challenges the hypothesis that RE must be inactivated in all cells for cell cycle progression to occur. Further characterization of this 'resistant' tumor line revealed that proliferation of these cells is still inhibited by PSM-RB. We show that this is due to PSM-RB-induced cell death. As such, these studies are the first to show that RE inhibits cellular proliferation through at least two distinct mechanisms - inhibition of cell cycle progression and induction of cell death.