CSN5 in Drosophila Oogenesis: Roles in Ecdysone Signaling and Border Cell Migration

csn5编码COP9信号体（CSN）的一个亚基，这是一个多亚基复合物，涉及多种以蛋白质稳定性和泛素依赖性降解为中心的细胞调节事件。在受调控的蛋白中，突出的是信号依赖性转录因子，如Jun、NFKB和核类固醇激素受体，以及细胞周期调节因子，如p27Kip1和p53（见Schwechheimer和Deng， 2001）。最近有研究表明，裂变酵母中的CSN5对应体调节了一种称为NEDD8的泛素样蛋白与E3泛素连接酶的连接（Lyapina et al, 2001）。因此，多种多样的CSN调控可以通过特定蛋白质的选择性降解或稳定来实现。在这里，becendorf博士对CSN在果蝇卵发生过程中对类固醇激素蜕皮激素的反应和边界细胞迁移中的作用特别感兴趣。该提案有三个具体目的：确定CSN5是否与蜕皮激素受体和TAIMAN共激活因子一起参与蜕皮激素反应。确定在调节边界细胞迁移时，CSN5是独立作用还是作为CSN复合体的一部分。确定CSN5（和CSN）是否通过nedd8 -泛素连接酶-蛋白酶体途径指导受体降解。这一建议对博士后、研究生和本科生的教育发展具有更广泛的影响。除了在实验室培养实验能力外，博士后和学生还参加每周的实验室会议、多实验室研究报告和期刊俱乐部。研究本身的更广泛的影响围绕着正常发育的控制和影响人类健康的疾病。泛素依赖性蛋白降解参与细胞周期、信号转导和抗原加工等基本细胞过程的调节。COP9信号小体是一种蛋白复合物，在信号转导和ub依赖性蛋白水解之间起作用。它控制的一些底物是至关重要的肿瘤抑制因子，如p53，或原癌基因，如p27kip1。在目前的建议中，我们研究了CSN对类固醇激素调节和细胞迁移的影响。对类固醇激素信号的精确控制是人类发育和繁殖所必需的。此外，一些最常见和最具破坏性的人类癌症，包括乳腺癌和前列腺癌，都依赖于类固醇激素信号。细胞迁移涉及胚胎模式、器官形成和免疫反应。侵袭性细胞迁移也是晚期肿瘤发生的一部分，包括正常组织的浸润和从肿瘤初始部位转移到体内其他组织。

SummaryCSN5 encodes one subunit of the COP9 signalosome (CSN), a multisubunit complex that has been implicated in a wide variety of cellular regulatory events centered around protein stability and ubiquitin-dependent degradation. Prominent among the regulated proteins are signal dependent transcription factors, such as Jun, NFKB, and the nuclear steroid hormone receptors, and cell cycle regulators like p27Kip1 and p53 (reviewed in Schwechheimer and Deng, 2001). It was recently shown that the CSN5 counterpart in fission yeast regulates the attachment of a ubiquitin-like protein called NEDD8 to E3 ubiquitin ligases (Lyapina et al, 2001). Thus, the wide variety of CSN regulation may be achieved by the selective degradation or stabilization of specific proteins. Here Dr. Beckendorf is particularly interested in the role of the CSN in the response to the steroid hormone ecdysone and in the migration of the border cells during Drosophila oogenesis. This proposal has three specific aims: Establish whether CSN5 participates in the ecdysone response along with the ecdysone receptor and the TAIMAN coactivator.Establish whether, in regulating the migration of border cells, CSN5 acts independently or as part of the CSN complex. Establish whether CSN5 (and the CSN) directs receptor degradation through the NEDD8-ubiquitin ligase-proteasome pathway.This proposal has broader impacts on the educational development of postdoctoral fellows, and both graduate and undergraduate students. In addition to developing their experimental abilities in the laboratory, both postdocs and students participate in weekly laboratory meetings and multi-laboratory research presentations and journal clubs. The broader impacts of the research itself center around the control of normal development and around diseases that affect human health. Ubiquitin-dependent protein degradation is involved in the regulation of essential cellular processes such as the cell cycle, signal transduction and antigen processing. The COP9 signalosome is a protein complex that acts at the intersection between signal transduction and Ub-dependent proteolysis. Some of the substrates it controls are crucial tumor suppressors, such as p53, or proto-oncogenes, such as p27kip1. In the current proposal we study the impact of the CSN on steroid hormone regulation and cell migration. Precise control of steroid hormone signaling is required for human development and reproduction. In addition, several of the most frequent and most devastating human cancers, including both breast and prostate cancer, are dependent on steroid hormone signaling. Cellular migrations are involved in embryonic patterning, organ formation, and immune responses. Invasive cell migrations are also part of late stage oncogenesis, including infiltration of normal tissues and metastatic spread from the initial site of the tumor to other tissues in the body.