Cell cycle regulation by protein phosphatase 2A

描述(申请人提供)：不适当的细胞增殖在许多病理环境中发生，包括癌症和动脉粥样硬化。哺乳动物的细胞周期受信号通路网络的调节，这些信号通路确保细胞分裂高保真地发生，并且只有在适当的条件下才能发生。这些通路中的许多都汇聚在细胞周期检查点，这些检查点控制着从一个阶段到下一个阶段的通道。检查点控制细胞从静止状态回到细胞周期的转变，以及从G1期到S期的转变。这些转变所需的两个蛋白质是视网膜母细胞瘤蛋白和细胞分裂周期6蛋白(CDC6)，视网膜母细胞瘤蛋白控制着G1进展所需的基因的表达，CDC6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的蛋白激酶和蛋白磷酸酶的协同作用的调节。最近的证据表明，钙调节的蛋白磷酸酶2A亚单位(PP2A)参与了这两种蛋白的去磷酸化。这个亚基(PR70)直接与视网膜母细胞瘤蛋白和CDC6相互作用，并通过靶向这些底物的PP2A催化成分来诱导它们的去磷酸化。钙对含PR70形式的PP2A的调控导致了一种新的信号机制的提出，该机制允许钙信号调节剂和诱导细胞增殖的剂之间的串扰。这项提议的目的是验证PP2A的PR70亚单位通过控制视网膜母细胞瘤蛋白和CDC6的去磷酸化来介导G1进展的钙调节的假设。 公共卫生相关性：在包括癌症和动脉粥样硬化在内的许多病理环境中，都会发生不适当的细胞增殖。哺乳动物的细胞周期受信号通路网络的调节，这些信号通路确保细胞分裂高保真地发生，并且只有在适当的条件下才能发生。最近的证据表明，细胞蛋白磷酸酶(PP2A)的一个钙调节亚单位参与了对调节细胞周期至关重要的蛋白质的去磷酸化。这项提议的目的是检验PP2A通过对这些蛋白质的作用介导钙依赖的细胞周期调节的假设。

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.