Cell cycle regulation by protein phosphatase 2A

描述（由申请人提供）：不适当的细胞增殖发生在许多病理情况下，包括癌症和动脉粥样硬化。哺乳动物的细胞周期是由信号通路网络调节的，这些信号通路确保细胞分裂在适当的条件下高保真地发生。许多这些途径都汇聚在细胞周期检查点上，这些检查点控制着从一个阶段到下一个阶段的传递。检查点控制着细胞从静止状态回到细胞周期以及从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，它控制G1进展所需基因的表达，以及细胞分裂周期6蛋白（Cdc6），这是在G1/S转变时启动DNA复制所必需的。这些蛋白的水平和活性受细胞周期调节蛋白激酶和蛋白磷酸酶的协同作用调节。最近的证据表明，蛋白磷酸酶2A （PP2A）的钙调节亚基参与了这两种蛋白的去磷酸化。该亚基（PR70）直接与视网膜母细胞瘤蛋白和Cdc6相互作用，并通过将PP2A的催化成分靶向到这些底物上诱导它们的去磷酸化。钙对含有pr70的PP2A形式的调控导致了一种新的信号传导机制的提出，该机制允许修饰钙信号传导的药物和诱导细胞增殖的药物之间的串扰。本研究的目的是验证PP2A的PR70亚基通过控制视网膜母细胞瘤蛋白和Cdc6的去磷酸化介导钙对G1进展的调节。

DESCRIPTION (provided by applicant): 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 proteins (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. PUBLIC HEALTH RELEVANCE: 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. Recent evidence has shown that a calcium-regulated subunit of a cellular protein phosphatase (PP2A) is involved in dephosphorylation of proteins that are critical for regulating the cell cycle. The goals of this proposal are to test the hypothesis that PP2A mediates calcium-dependent regulation of the cell cycle through actions on these proteins.