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NUCLEAR PL SCRAMBLASE IN DIFFERENTIATION & APOPTOSIS

核电 PL Scramblase 的差异化

基本信息

批准号：
7645728
负责人：
PETER J SIMS
金额：
$ 36.98万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7645728
关键词：
Amino Acids Apoptosis Apoptotic Back Binding Biological Assay Blood Blood Cells CSF3 gene Cell Line Cell Nucleus Cell Proliferation Cell membrane Cells Cholesterol Chromatin Complementary DNA Complex Consensus DNA DNA Binding DNA Sequence DNA-Binding Proteins Data Deoxyribonucleases Digestion Dimerization Exhibits Family Genes Genetic Transcription Genomics Goals Granulopoiesis Growth Factor Hematopoietic In Vitro Length Leucine Leucine Zippers Leukocytes Leukocytosis Mediating Membrane Membrane Lipids Membrane Microdomains Membrane Proteins Molecular Movement Mus Mutation Myelogenous Nuclear Nuclear Import Nuclear Localization Signal Nucleotides Peptide Signal Sequences Peptides Phenotype Phosphatidylserines Phospholipids Principal Investigator Process Protein Family Proteins Receptor Signaling Regulator Genes Reporting Resistance Sodium Chloride Sphingomyelins Structure System Transcriptional Activation Transfection Yeasts alpha Karyopherins cell injury cytokine granulocyte macrophage mutant phospholipid scramblase polypeptide prevent programs receptor research study response success three dimensional structure trafficking transcription factor

项目摘要

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(申请人提供)：磷脂加扰酶1(PLSCR1)是四个保守的钙结合、多棕榈酸化的界面质膜蛋白家族之一，被认为有助于磷脂酰丝氨酸和其他膜磷脂在细胞损伤和凋亡后的跨双层运动。我们最近发现PLSCR1的表达是由几种细胞因子转录诱导的，其中包括已知的调节细胞增殖和成熟的生长因子，这种细胞PLSCR1的增加似乎是正常增殖和髓系前体细胞向粒细胞或巨噬细胞终末分化所必需的。这种新合成的PLSCR1的一个成分定位在细胞核内，当多肽未能棕榈酰化时，就会发生PLSCR1的核输入，这是其膜保持所需的。我们最近还发现，PLSCR1的核输入是由Importin-核孔运输系统主动介导的，反映了蛋白质中发现的非常规核定位信号。相反，棕榈酰化的PLSCR1是质膜脂“筏”的一个组成部分，膜微域被认为参与了受体信号平台的组装和质膜上激活的受体的内向运输。在这一应用中，我们重点研究血液和其他细胞中核PL扰乱酶的功能，总体目标是确定PLSCR1表达的诱导及其在α/β介导的核内转运对其他基因表达的影响，这些基因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。具体目标包括(1)推断PLSCRI/Importin-α复合体的结构并确定控制它们相互作用的关键残基；(2)确定核PLSCR1的靶DNA序列和具有基因调控功能的潜在结合基序；(3)确定PLSCR1中的DMA结合结构域；以及(4)鉴定其转录受核PLSCR1调控的基因，并确定其基因产物细胞表达变化的功能后果。