Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells.
Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells.
复制标题
极性和增殖受到乳腺上皮肿瘤细胞下游的不同信号通路的控制。
DOI：
10.1083/jcb.200306090
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发表时间：
2004-02-16
影响因子：
7.8
通讯作者：
Bissell, Mina J
中科院分区：
文献类型：
--
作者：
Liu, Hong;Radisky, Derek C;Wang, Fei;Bissell, Mina J
组织极性丧失和增殖增加是乳腺肿瘤表型的特征性改变。为了研究这些过程，我们使用了三维（3D）培养系统，其中恶性人类乳腺细胞可以通过暴露于磷脂酰肌醇3-激酶（PI 3 K）抑制剂而恢复到正常表型。使用该测定，我们发现Akt和Rac 1作为PI 3 K的下游效应物，分别作为细胞增殖和组织极性的控制点。我们的研究结果还表明，PI 3 K信号通路是三维生长诱导的整体信号网络的组成部分，因为抑制PI 3 K信号通路影响的逆转也下调了PI 3 K上游调节剂β1整联蛋白和表皮生长因子受体的内源性水平，并上调了PI 3 K拮抗剂PTEN。这些发现揭示了PI 3 K通路的关键事件，其在维持组织极性方面发挥独特作用，并且当被破坏时有助于恶性表型。
Loss of tissue polarity and increased proliferation are the characteristic alterations of the breast tumor phenotype. To investigate these processes, we used a three-dimensional (3D) culture system in which malignant human breast cells can be reverted to a normal phenotype by exposure to inhibitors of phosphatidylinositol 3-kinase (PI3K). Using this assay, we find that Akt and Rac1 act as downstream effectors of PI3K and function as control points of cellular proliferation and tissue polarity, respectively. Our results also demonstrate that the PI3K signaling pathway is an integral component of the overall signaling network induced by growth in 3D, as reversion affected by inhibition of PI3K signaling also down-modulates the endogenous levels of β1 integrin and epidermal growth factor receptor, the upstream modulators of PI3K, and up-regulates PTEN, the antagonist of PI3K. These findings reveal key events of the PI3K pathway that play distinct roles to maintain tissue polarity and that when disrupted are instrumental in the malignant phenotype.