NUCLEAR PL SCRAMBLASE IN DIFFERENTIATION & APOPTOSIS

核电 PL Scramblase 的差异化

• 批准号: 7213130
• 负责人: PETER J SIMS
• 金额: $ 18.28万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213130
• 关键词: apoptosis; cell differentiation; flow cytometry; gene targeting; genetically modified animals; growth inhibitors; laboratory mouse; membrane activity; membrane proteins; membrane structure; phosphatidylserines; phospholipids; reticuloendothelial system; tissue /cell culture

DESCRIPTION (provided by applicant): Phospholipid scramblase 1 (PLSCR1) is one of a family of four conserved Ca -binding, multiply-palmitoylated, endofacial plasma membrane proteins thought to contribute to the transbilayer movement of phosphatidylserine and other membrane phospholipids following cell injury and apoptosis. We recently discovered that expression of PLSCR1 is transcriptionally induced by several cytokines, including growth factors known to regulate cellular proliferation and maturation, and such increase in cellular PLSCR1 appears required for normal proliferation and terminal differentiation of myeloid precursors into granulocytes or macrophages. A component of this newly synthesized PLSCR1 localizes within the nucleus, and nuclear import of PLSCR1 was found to occur whenever the polypeptide failed to palmitoylate, as required for its membrane retention. We also recently showed that nuclear import of PLSCR1 is actively mediated by the importin-nucleopore transport system, reflecting an unconventional nuclear localization signal identified in the protein. By contrast, palmitoylated PLSCR1 is a component of plasma membrane lipid "rafts", membrane microdomains believed to be involved in both assembly of receptor signaling platforms and endocytic trafficking of activated receptors from the plasma membrane. In this application, we focus on the function of nuclear PL scramblase in blood and other cells, with the overall goal of determining how induction of the expression of PLSCR1 and its importinalpha/beta-mediated transport into the nucleus impacts upon the expression of other genes potentially involved in regulating proliferative, maturational and apoptotic responses of leukocytes and other blood cells to growth factors and related cytokines. Specific Aims include (1) to deduce the structure of the PLSCRI/importin-alpha complex and to identify key residues controlling their interaction; (2) to identify target DNA sequence of nuclear PLSCR1 and potential binding motifs with gene regulatory function; (3) to identify the DMA-binding domain in PLSCR1; & (4) to identify those genes whose transcription is regulated by nuclear PLSCR1 and to determine the functional consequence of resulting change in cellular expression of their gene products.

描述（由申请人提供）：磷脂爬行酶1（PLSCR 1）是四种保守的Ca结合、多棕榈酰化、内表面质膜蛋白家族之一，被认为有助于细胞损伤和凋亡后磷脂酰丝氨酸和其他膜磷脂的跨双层运动。我们最近发现，PLSCR 1的表达是转录诱导的几种细胞因子，包括已知的生长因子调节细胞增殖和成熟，并在细胞PLSCR 1的这种增加似乎需要正常增殖和终末分化的骨髓前体成粒细胞或巨噬细胞。这种新合成的PLSCR 1的一个组成部分定位在细胞核内，PLSCR 1的核输入被发现发生时，多肽未能棕榈酰化，所需的膜保留。我们最近还表明，PLSCR 1的核输入是由输入-核孔转运系统主动介导的，反映了在蛋白质中鉴定的非常规核定位信号。相比之下，棕榈酰化PLSCR 1是质膜脂质“筏”的组分，膜微结构域被认为参与受体信号平台的组装和活化受体从质膜的内吞运输。在本申请中，我们专注于核PL乱序酶在血液和其他细胞中的功能，总体目标是确定PLSCR 1的表达的诱导及其importinalpha/beta介导的向细胞核的转运如何影响可能参与调节白细胞和其他血细胞对生长因子和相关细胞因子的增殖、成熟和凋亡反应的其他基因的表达。具体目的包括：（1）推断PLSCR 1/importin-alpha复合物的结构，并鉴定控制它们相互作用的关键残基;（2）鉴定核PLSCR 1的靶DNA序列和潜在的具有基因调控功能的结合基序;（3）鉴定PLSCR 1的DMA结合结构域;（4）鉴定那些转录受核PLSCR 1调控的基因，并确定其基因产物细胞表达变化的功能后果。