The overall objective is to characterize the Drosophila melanogaster gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and its regulation. Mevalonate is the product of the reductase and a precursor for many polyisoprenoids that are required for cell growth and development. These include dolichol, ubiquinone, the isopentenyl group of isopentenyl tRNA's and in insects, juvenile hormones (JH). While the vertebrate reductase is a """"""""housekeeping"""""""" gene regulated by a complex multivalent feedback system (mediated by both sterol and non-sterol metabolites derived from mevalonate), regulation of the insect reductase is (1) simple and (2) likely to exhibit tissue specific expression in the corpus allatum, the principle site of JH synthesis. Elucidation of the mechanisms that regulate developmental and tissue specific expression of the insect reductase will clarify the relationship between isoprenoid and sterol regulation of the vertebrate reductase and thus contribute to our understanding of the mammalian system. These studies will begin with the isolation of the fly reductase gene, structural comparisons of the fly enzyme and promotor to the corresponding hamster enzyme and promotor, and will be followed by expression studies using promotor fusions transfected into cultured fly and/or vertebrate cells. The second major emphasis of this proposal will be to study the temporal and tissue specificity of reductase expression in the developing fly. These studies, in turn, will comprise the background from which we will begin to isolate mutations in the regulatory apparatus of the reductase gene. Thus, we hope to exploit both genetic and developmental features of this model organism to unravel the regulation of this metabolic pathway.
| Gertler, F B; Chiu, C Y; Richter-Mann, L et al. (1988) Developmental and metabolic regulation of the Drosophila melanogaster 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mol Cell Biol 8:2713-21 |
