Cell cycle regulation by protein phosphatase 2A

蛋白磷酸酶 2A 的细胞周期调节

• 批准号: 8019096
• 负责人: Marc C. MUMBY
• 金额: $ 30.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019096
• 关键词: Affect; Affinity; Atherosclerosis; Back; Binding Sites; Calcium; Calcium Binding; Calcium Signaling; Cell Cycle; Cell Cycle Proteins; Cell Cycle Regulation; Cell Proliferation; Cell division; Cells; Chromatin; Complex; DNA Replication Factor; DNA biosynthesis; Ensure; G1/S Transition; Gene Expression; Goals; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Pre-Replication Complex; Protein Dephosphorylation; Protein Kinase; Protein phosphatase; Proteins; RNA Interference; Regulation; Replication Initiation; Resistance; Retinoblastoma Protein; Role; S Phase; Signal Pathway; Signal Transduction; Specificity; Staging; Structure; Testing; base; dimer; novel; public health relevance; research study

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.

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。哺乳动物细胞周期受到信号通路网络的调节，确保细胞分裂仅在适当的条件下以高保真度发生。许多这些途径汇聚在控制从一个阶段到下一阶段的通道的细胞周期检查点上。检查点控制细胞从静止状态转变回细胞周期以及从G1期转变为S期。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)，它是在 G1/S 转变时启动 DNA 复制所必需的。这些蛋白质的水平和活性受到细胞周期调节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，蛋白磷酸酶 2A (PP2A) 的钙调节亚基参与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 的催化成分靶向这些底物来诱导其去磷酸化。钙对含有 PR70 形式的 PP2A 的调节提出了一种新的信号传导机制，该机制允许修饰钙信号传导的药物与诱导细胞增殖的药物之间进行串扰。该提案的目的是检验以下假设：PP2A 的 PR70 亚基通过控制视网膜母细胞瘤蛋白和 Cdc6 的去磷酸化来介导 G1 进展的钙调节。 公共卫生相关性：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。哺乳动物细胞周期受到信号通路网络的调节，确保细胞分裂仅在适当的条件下以高保真度发生。最近的证据表明，细胞蛋白磷酸酶 (PP2A) 的钙调节亚基参与对调节细胞周期至关重要的蛋白质的去磷酸化。该提案的目的是检验以下假设：PP2A 通过作用于这些蛋白质来介导细胞周期的钙依赖性调节。