| Dorsal is a morphogen essential for specification of the dorsoventral axis of the Drosophila embryo. It belongs to the Rel family of transcription factors, which also includes Drosophila immune regulator Dif and Relish, the mammalian Rel/NF-κB proteins, and the avian oncogene v-rel. All the members in the family share similarity in structure and mode of action and regulation. The activation of Rel proteins depends on a signal transduction pathway known as Rel pathway. The Rel pathway is evolutionarily conserved in invertebrates and vertebrates. In mammals it participates in the immune and inflammatory responses, and is critical for cell growth and survival. In Drosophila, it functions in the formation of the dorsal-ventral polarity in the early embryo and in the innate immune response in larvae and adults.; In order to identify additional proteins functioning in the Drosophila Rel pathway, I performed a yeast two-hybrid interaction screen of an ovarian cDNA library using the Dorsal Rel homology region (RHR) as bait. I identified a previously unknown interaction between Dorsal and Tube which was further confirmed in an in vitro binding assay. Genetic experiments suggested that Tube-Dorsal interaction is essential for normal signal transduction. Furthermore, I found that Pelle also interacts with Dorsal. I proposed a model in which Tube, Pelle, Cactus and Dorsal form a multimeric complex in signal transduction.; Several other putative PER interacting partners were identified in the same screen. One of them, Tamo, represents a novel protein, and has been shown to have an important regulatory function in the nuclear transport of Dorsal. Other candidates, including Drosophila Menin, Drosophila metal-responsive transcription factor (MTF-1) and Drosophila aminopeptidase, are being further investigated.; The Rel pathway has been implicated in various common human diseases. In the last chapter of this thesis, I reviewed the important roles of the Rel pathway in the pathogenesis of several human diseases, as well as its potential therapeutic values. |
