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

University Of California-Berkeley, Berkeley CA

Investigators

Abstract

Summary CSN5 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.