E-cadherin mediates aggregation-dependent survival of prostate and mammary epithelial cells through the retinoblastoma cell cycle control pathway
E-cadherin mediates aggregation-dependent survival of prostate and mammary epithelial cells through the retinoblastoma cell cycle control pathway
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DOI：
10.1074/jbc.274.14.9656
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发表时间：
1999-04-02
影响因子：
4.8
通讯作者：
Day, KC
中科院分区：
文献类型：
--
作者：
Day, ML;Zhao, X;Day, KC
传统上，E-钙粘蛋白和视网膜母细胞瘤肿瘤抑制因子（Rb）与细胞生长和分化的不同调节方面相关，然而，我们发现了新的证据，这表明这些蛋白质在细胞存活和程序性细胞死亡所需的生理途径中功能性地连接。蛋白激酶C（PKC）的药理学活化或PRC的α同工酶（PHC α）的诱导性过表达和活化导致约60%的乳腺和前列腺上皮细胞凋亡。有趣的是，存活的细胞经历了显著的聚集，同时E-钙粘蛋白表达增加。当通过添加E-钙粘蛋白阻断抗体抑制聚集时，细胞凋亡协同增加。我们假设聚集群体的存活与接触抑制生长相关，并且细胞凋亡可能是由非聚集的循环细胞中的异常生长调节信号引起的。这一假设得到证实的实验表明，E-钙粘蛋白依赖性聚集导致Rb介导的GI逮捕和生存，免疫印迹分析和弓流式细胞术显示，低磷酸化Rb是目前在非聚集，S期培养协同细胞死亡。我们还确定，膜E-钙粘蛋白的损失和随后的低磷酸化的Rb在管腔上皮细胞凋亡诱导去势。这些发现提供了令人信服的证据，表明E-钙粘蛋白介导的聚集导致Rb激活和G（1）阻滞，这对前列腺和乳腺上皮细胞的存活至关重要。这些数据还表明，当这些上皮细胞进入S期时，当蛋白质低磷酸化时，Rb可以在非聚集的周期细胞中引发致命的生长信号冲突。
E-cadherin and the retinoblastoma tumor suppressor (Rb) are traditionally associated with diverse regulatory aspects of cell growth and differentiation, However, we have discovered new evidence, which suggests that these proteins are functionally linked in a physiologic pathway required for cell survival and programmed cell death. pharmacological activation of protein kinase C (PKC) or inducible overexpression and activation of the alpha isozyme of PRC (PHC alpha) resulted in approximately 60% apoptosis of mammary and prostate epithelial cells, Interestingly, the surviving cells had undergone dramatic aggregation concurrent with increased E-cadherin expression. When aggregation was inhibited by the addition of an E-cadherin-blocking antibody, apoptosis increased synergistically, We hypothesized that survival of the aggregated population was associated with contact-inhibited growth and that apoptosis might result from aberrant growth regulatory signals in non-aggregated, cycling cells. This hypothesis was confirmed by experiments that demonstrated that E-cadherin-dependent aggregation resulted in Rb-mediated GI arrest and survival, Immunoblot analysis and Bow cytometry revealed that hypophosphorylated Rb was present in non-aggregated, S phase cultures concurrent with synergistic cell death. We have also determined that the loss of membrane E-cadherin and subsequent hypophosphorylation of Rb in luminal epithelial cells preceded apoptosis induced by castration. These findings provide compelling evidence that suggests that E-cadherin-mediated aggregation results in Rb activation and G(1), arrest that is critical for survival of prostate and mammary epithelial cells, These data also indicate that Rb can initiate a fatal growth signal conflict in non-aggregated, cycling cells when the protein is hypophosphorylated as these epithelial cells enter S phase.