FUNCTIONS OF APOLIPOPROTEINS IN CANCER APOPTOSIS

载脂蛋白在癌症细胞凋亡中的功能

• 批准号: 7381757
• 负责人: Chien-An Andy Hu
• 金额: $ 5.53万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381757
• 关键词: FUNCTIONS; APOLIPOPROTEINS; CANCER; APOPTOSIS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer cells frequently possess defects in the genetic and biochemical pathways of programmed cell death (PCD). Members of the Bcl-2 family play pivotal roles regulating two types of PCD in mammals: apoptosis and autophagy. It is evident that the BH3 domain-only members of the Bcl-2 family regulate di- and or oligo-merization of the Bcl-2 family members through protein-protein interaction and therefore induce apoptosis. However, the role of the BH3 domain-only proteins in autophagic cell death has not been fully explored. The completion of the Human Genome Project and the availability of various public databases and sequence analysis algorithms allowed us to utilize the bioinformatic data-mining approach to identify two novel BH3-only proteins, apolipoprotein L6 (ApoL6) and ApoL1. Previously we showed that overexpression of wild-type ApoL6 induced mitochondria-mediated apoptosis in DLD-1 cells as characterized by release of cytochrome c and Smac/DIABLO from mitochondria and activation of caspase 9, whereas ApoL6 BH3 domain deletion allele did not. Surprisingly, our recent results showed that ApoL1, a closely related protein of ApoL6, induced autophagic, rather than apoptotic, cell death in cancer cells as characterized by activation and translocation of LC3, and formation of vacuoles/autophagosomes. Inhibitors of autophagy block ApoL1-induced cell death. To our knowledge, this is the first example that intracellular overproduction of an apolipoprotein (ApoL1), which possesses a BH3-only domain, induces autophagic cell death. In addition, to explore genomic structure and functional motifs of ApoL1 and ApoL6, we have continued using biocomputing strategy to analyze exon-intron boundaries (DNA), transcript variants (RNA), protein isoforms and protein motifs/domains of ApoL1 and ApoL6. Furthermore, we have expanded this project to study the genomic structure and functional motifs of ApoL2 and ApoL3, two other members of ApoLs, which could potentially play important roles in cancer cell death.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。癌细胞经常在程序性细胞死亡（PCD）的遗传和生化途径中存在缺陷。 Bcl-2家族的成员扮演着调节哺乳动物两种类型的PCD的关键作用：凋亡和自噬。显然，BCl-2家族的仅BH3结构域成员通过蛋白质 - 蛋白质相互作用调节Bcl-2家族成员的DI-和 /或 /或寡核化，从而诱导凋亡。然而，尚未完全探索仅BH3域蛋白在自噬细胞死亡中的作用。人类基因组项目的完成以及各种公共数据库的可用性和序列分析算法使我们能够利用生物信息学数据挖掘方法来识别两种新型BH3仅仅BH3蛋白质蛋白，载脂蛋白L6（ApoL6）和Apol1。以前，我们表明，野生型Apol6的过表达诱导的线粒体介导的DLD-1细胞中的线粒体介导的凋亡，其特征是从线粒体中释放了细胞色素C和SMAC/DIABLO，而caspase 9的激活以及Apol6 Bh3域的deletele等位基因却没有。令人惊讶的是，我们最近的结果表明，APOL1是一种密切相关的APOL6蛋白，诱导自噬，而不是凋亡，癌细胞中的细胞死亡，其特征是LC3的激活和易位，以及液泡/自噬体的形成。自噬块APOL1诱导的细胞死亡的抑制剂。据我们所知，这是第一个例子，即具有仅BH3域的载脂蛋白（Apol1）的细胞内过量生产（Apol1）会诱导自噬细胞死亡。此外，为了探索APOL1和APOL6的基因组结构和功能基序，我们继续使用生物计算策略来分析外显子内边界（DNA），转录物变体（RNA），蛋白质同工型和ApoL1和ApoL6的蛋白质基序和蛋白质基序。此外，我们扩展了该项目，以研究Apol2和Apol3的基因组结构和功能基序，这是APOL的另外两个成员，这可能在癌细胞死亡中起重要作用。