Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Cancer Res. 2010 Dec 15;70(24):10474-84. doi: 10.1158/0008-5472.CAN-10-2855.
The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine-threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56α, B56γ, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56α, B56γ, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation.
猿猴病毒 40 小 t（SV40ST）癌蛋白与蛋白磷酸酶 2A（PP2A）相互作用，PP2A 是一种丰富表达的丝氨酸-苏氨酸磷酸酶家族。这种相互作用对于 SV40 转化人类细胞是必不可少的，并且已经有几个 PP2A 亚基被认为是肿瘤抑制基因。然而，参与细胞转化的特定 PP2A 复合物所控制的途径仍不完全清楚。我们使用全面的功能丧失方法，鉴定出 4 种 PP2A 调节亚基[B56α、B56γ、PR72/PR130 和 PTPA（蛋白磷酸酶 2A 激活剂）]，当这些亚基被抑制时，它们可以替代 SV40ST 在人类细胞转化中的表达。我们发现，操纵含有 PP2A B56α、B56γ 和 PR72/PR130 的复合物会以依赖于其特定磷酸酶活性的方式激活 c-Myc、Wnt 和 PI3K（磷酸肌醇 3-激酶）/Akt 调节的途径。相比之下，抑制 PTPA 会破坏 PP2A 异三聚体复合物的组装，从而导致这些相同的致癌途径被激活。这些观察结果描绘了 SV40ST 在人类细胞转化过程中扰动的 PP2A 家族成员和途径。
