Cell cycle regulation by protein phosphatase 2A

不适当的细胞增殖发生在许多病理环境中，包括癌症和动脉粥样硬化。的 哺乳动物的细胞周期是由一个信号通路网络调节的，该网络确保细胞分裂以高的 只有在适当的条件下，才能保持忠诚。这些途径中的许多都集中在细胞周期检查点上， 从一个阶段到下一个阶段的控制通道。检查点控制单元从静止状态返回 进入细胞周期和从G1期到S期的转变。这些转变所需的两种蛋白质是 视网膜母细胞瘤蛋白，控制G1期进展和细胞分裂所需的基因表达 周期6蛋白（Cdc 6），其在G1/S转换时启动DNA复制所需。水平和 这些蛋白质的活性受细胞周期调节蛋白激酶的协同作用调节， 蛋白磷酸酶最近的证据表明，蛋白磷酸酶2A的钙调节亚基 （PP 2A）参与这两种蛋白质的去磷酸化。该亚基（PR 70）直接与 视网膜母细胞瘤蛋白和Cdc 6，并通过靶向视网膜母细胞瘤蛋白的催化成分诱导其去磷酸化。 PP 2A与这些底物。钙对含PR 70形式的PP 2A的调节导致了以下建议： 一种新的信号传导机制，其允许在修饰钙信号传导的试剂和 诱导细胞增殖。本研究的目的是验证PP 2A的PR 70亚基 通过控制视网膜母细胞瘤蛋白的去磷酸化来介导钙对G1期进展的调节 Cdc6。

Inappropriate cell proliferation occurs in many pathological settings including cancer and atherosclerosis. The mammalian cell cycle is regulated by a network of signaling pathways that ensure cell division occurs with high fidelity and only under appropriate conditions. Many of these pathways converge on cell cycle check points that control passage from one stage to the next. Check points control the transition of cells from a quiescent state back into the cell cycle and the transition from G1 into S phase. Two proteins required for these transitions are the retinoblastoma protein, which controls the expression of genes required for G1 progression and the cell division cycle 6 protein (Cdc6), which is required for initiating DNA replication at the G1/S transition. The level and activities of these proteins are regulated by the concerted actions of cell cycle regulated protein kinases and protein phosphatases. Recent evidence has shown that a calcium-regulated subunit of protein phosphatase 2A (PP2A) is involved in dephosphorylation of both of these proteins. This subunit (PR70) directly interacts with the retinoblastoma protein and Cdc6, and induces their dephosphorylation by targeting the catalytic components of PP2A to these substrates. The regulation of the PR70-containing form of PP2A by calcium has led to proposal of a novel signaling mechanism that allows cross-talk between agents that modify calcium signaling and agents that induce cell proliferation. The goals of this proposal are to test the hypothesis that the PR70 subunit of PP2A mediates calcium regulation of G1 progression by controlling the dephosphorylation of the retinoblastoma protein and Cdc6.