Ribosomal RNA synthesis and the regulation of cell growth. S.S. Grewal , J. Evans , B.A. Edgar. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

   Regulation of protein synthesis and ribosome biogenesis is thought to be a critical component of cell growth control mechanisms. Extensive work in eukaryotes has identified growth signaling pathways that regulate translation factors and ribosomal protein synthesis. However, surprisingly little work has focused on the regulation of rRNA synthesis as a target for growth signals. As such, we are currently testing the role of rRNA synthesis in the control of cell growth in Drosophila. Our studies indicate that rRNA synthesis is rapidly and markedly stimulated during larval development by treatments that augment growth, such as changes in dietary protein and overexpression of dMyc or CycD/cdk4. In contrast, activation of insulin/PI3 kinase signaling has no effect on rRNA synthesis. We are currently determining whether reducing rRNA levels limits the effects induced by these different signals using mutants that affect either RNA Polymerase I (Pol I) activity or rRNA processing. In addition, we are using a GAL4 responsive UAS-rDNA transgene to examine whether stimulation of rRNA synthesis can increase ribosome biogenesis and augment growth. We are also attempting to identify Pol I-dependent transcription factors that are targets of growth signaling pathways. Among all known eukaryotic regulators of rRNA transcription, TIF-IA (known as rrn3 in yeast) is perhaps the best candidate growth-regulated factor. We have identified a Drosophila homologue of TIF-IA. Our studies indicate that dMyc and changes in dietary protein regulate larval TIF-IA transcript levels. We are currently using both GAL4/UAS-transgene and RNAi approaches to study the function of TIF-IA in larval growth. Together, the studies outlined above should present a detailed investigation of how rRNA synthesis is stimulated and the role it plays in cell growth may therefore provide insight into an, as yet, unexplored component of the cell growth control machinery.