Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain.
Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain.
复制标题
病毒肿瘤抗原逆转抗雌激素介导的 MCF-7 细胞细胞周期停滞需要视网膜母细胞瘤蛋白结合结构域。
DOI：
10.1038/sj.onc.1203827
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Conrad,SE
中科院分区：
文献类型：
--
作者：
Varma,H;Conrad,SE
MCF-7细胞的增殖具有雌激素依赖性和抗雌激素敏感性。在不存在雌激素或存在抗雌激素的情况下，MCF-7细胞停滞在细胞周期的G1期，并且这种停滞与成视网膜细胞瘤蛋白（pRb）的活性低磷酸化形式的积累有关。由于活性pRb负调控通道从G1期到S期，这表明，pRb是一个关键的目标雌激素的作用，它的失活可能会导致抗雌激素抵抗。我们通过在MCF-7细胞中表达病毒肿瘤抗原（T抗原）来验证这一假设，T抗原结合和抑制pRb，并确定在抗雌激素存在下对细胞增殖的影响。这些实验的结果证明T抗原表达赋予MCF-7细胞抗雌激素抗性。使用一组突变的T抗原，我们进一步证明，pRb结合，但不是p53结合域是必需的，赋予抗雌激素抗性。因此，pRb是雌激素作用的一个重要靶点，其失活可导致抗雌激素抗性的发展。
Proliferation of MCF-7 cells is estrogen dependent and antiestrogen sensitive. In the absence of estrogens or presence of antiestrogens MCF-7 cells arrest in the G 1 phase of the cell cycle, and this arrest is associated with an accumulation of the active, hypophosphorylated form of the retinoblastoma protein (pRb). Because active pRb negatively regulates passage from G 1 to S phase, this suggests that pRb is a crucial target of estrogen action, and that its inactivation might lead to antiestrogen resistance. We tested this hypothesis by expressing viral tumor antigens (T antigens), which bind and inactivate pRb, in MCF-7 cells, and determining the effects on cell proliferation in the presence of antiestrogens. The results of these experiments demonstrate that T antigen expression confers antiestrogen resistance to MCF-7 cells. Using a panel of mutant T antigens, we further demonstrate that the pRb-binding, but not the p53 binding domain is required to confer antiestrogen resistance. Thus, pRb is an important target of estrogen action, and its inactivation can contribute to the development of antiestrogen resistance.