Mechanism of apoptosis induction by the receptor DCC

DCC受体诱导细胞凋亡的机制

• 批准号: 7172574
• 负责人: Dale E. Bredesen
• 金额: $ 32.29万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172574
• 关键词: 18q; Adaptor Signaling Protein; Adult; Amino Acids; Androgen Receptor; Antibodies; Apoptosis; Apoptotic; Axon; Binding; Biological Assay; Brain Stem; Caspase; Cell Communication; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Chromosomes, Human, Pair 2; Cleaved cell; Co-Immunoprecipitations; Colon Carcinoma; Colorectal Cancer; Complement; Complex; Cues; Cytoplasmic Granules; DCC gene; Data; Dependence; Development; Disease; Dominant-Negative Mutation; Extracellular Matrix; Goals; Growth; Growth Cones; Homologous Gene; Hybrids; IGF1R gene; In Vitro; Induction of Apoptosis; Insulin-Like-Growth Factor I Receptor; Knock-in Mouse; Knock-out; Knockout Mice; Ligands; Loss of Heterozygosity; Malignant Neoplasms; Mediating; Membrane; Metastasis Suppression; Mitochondria; Molecular; Molecular Analysis; Monitor; Mutant Strains Mice; Mutate; Mutation; N-terminal; NGFR gene; Nature; Nerve; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nerve Growth Factor Receptors; Nervous system structure; Neuraxis; Neurites; Neurons; Numbers; Pathway interactions; Phage Display; Phenotype; Physiological; Process; Proteins; Regulation; Reporting; Research; Research Personnel; Retinal Cone; Role; Signal Transduction; Site; System; Techniques; Time; Transfection; Tumor Suppressor Proteins; Wild Type Mouse; Withdrawal; apoptosis inducing factor; apoptotic protease-activating factor 1; aposome; axon guidance; base; caspase-8; caspase-9; concept; cytokine; dalton; experience; human NTN1 protein; in vivo; interest; member; mutant; nervous system development; netrin receptor; netrin-1; neurodevelopment; novel; receptor; tissue culture; transcription factor; tumor; tumor progression; yeast two hybrid system

DESCRIPTION (provided by applicant): The androgen receptor, RET (REarranged during Transfection), DCC (Deleted in Colorectal Cancer), and UNC5H1-3 (Unc-5 homologues 1-3) are members of a growing list of dependence receptors. Such receptors, by inducing apoptosis when expressed in a setting in which their ligands are unavailable, create a cellular state of dependence on their ligands for survival. Of interest is that all of these receptors are involved in cancer progression, central nervous system-associated diseases and/or development of the nervous system. As an example, DCC encodes a potential tumor suppressor but at the same time is a key receptor in mediating axon guidance induced by the cue netrin-1. By focusing our study on DCC, we propose to define (i) the molecular mechanisms allowing the induction of apoptosis in the absence of ligand, and those mechanisms that block apoptosis in the presence of ligand, (ii) the in vivo function of these dependence receptors, and specifically in the case of DCC, the role of DCC-induced apoptosis inaxon guidance during nervous system development. We will define the molecular mechanisms startingfrom our initial observation that DCC serves as the core for a complex allowing caspase activation.Experiments will include two-hybrid studies using the pro-apoptotic region of DCC (amino acids 1121-1290) as bait, purification and characterization of the proteins contained in the 800,000 Dalton complexformed with DCC, and determination of the presence and the role of DCC multimerization. The in vivo relevance of the pro-apoptotic effect of DCC will be studied by monitoring DCC cleavage by caspasesduring development of the nervous system and by creating knock-in mice expressing a mutated form ofDCC that is unable to induce apoptosis.

描述（由申请人提供）：雄激素受体、RET（转染期间重排）、DCC（结直肠癌中删除）和 UNC5H1-3（Unc-5 同源物 1-3）是不断增长的依赖性受体列表中的成员。当这些受体在其配体不可用的环境中表达时，通过诱导细胞凋亡，产生依赖于其配体生存的细胞状态。有趣的是，所有这些受体都参与癌症进展、中枢神经系统相关疾病和/或神经系统的发育。例如，DCC 编码一种潜在的肿瘤抑制因子，但同时也是介导由提示 netrin-1 诱导的轴突引导的关键受体。通过将我们的研究重点放在DCC上，我们建议定义（i）在没有配体的情况下诱导细胞凋亡的分子机制，以及在配体存在的情况下阻止细胞凋亡的那些机制，（ii）这些依赖性的体内功能受体，特别是在 DCC 的情况下，DCC 诱导的细胞凋亡在神经系统发育过程中的作用。我们将从我们最初的观察开始定义分子机制，即 DCC 作为允许 caspase 激活的复合物的核心。实验将包括使用 DCC 促凋亡区域（氨基酸 1121-1290）作为诱饵、纯化和对与 DCC 形成的 800,000 道尔顿复合物中所含蛋白质进行表征，并确定 DCC 多聚化的存在及其作用。将通过监测神经系统发育过程中半胱天冬酶对 DCC 的裂解以及通过创建表达不能诱导细胞凋亡的突变形式的 DCC 的敲入小鼠来研究 DCC 促细胞凋亡作用的体内相关性。

项目成果

Novel mediators of amyloid precursor protein signaling.

• DOI: 10.1523/jneurosci.4351-09.2009
• 发表时间: 2009-12-16
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Swistowski A;Zhang Q;Orcholski ME;Crippen D;Vitelli C;Kurakin A;Bredesen DE
• 通讯作者: Bredesen DE

The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex.

Patched 依赖性受体通过 DRAL-caspase-9 复合物触发细胞凋亡。

• DOI: 10.1038/ncb1880
• 发表时间: 2009-06
• 期刊: NATURE CELL BIOLOGY
• 影响因子: 21.3
• 作者: Mille, Frederic;Thibert, Chantal;Fombonne, Joanna;Rama, Nicolas;Guix, Catherine;Hayashi, Hideki;Corset, Veronique;Reed, John C.;Mehlen, Patrick
• 通讯作者: Mehlen, Patrick