Mutation of the gene encoding the ubiquitin activating enzyme ubal causes tissue overgrowth in Drosophila.

Protein ubiquitination has been shown to regulate a wide variety of cellular process including cell cycle progression, protein trafficking and apoptosis. Most regulation of ubiquitination occurs at the level of E2 or E3 enzymes and their interactions with specific substrates. In a screen for mutations that cause tissue overgrowth, we recovered multiple mutations in the Drosophila Uba1 gene that encodes the E1 enzyme that is required for the first step of most, if not all, ubiquitination reactions. Previous studies with yeast and mammalian cells have shown that disrupting E1 function results in a cell-cycle arrest. Here we show that in the developing Drosophila eye, clones of cells that are homozygous for partial loss of function alleles of Uba1 show defects in apoptosis. Moreover, clones homozygous for stronger or complete loss of function alleles of Uba1, that are predicted to have a global defect on ubiquitination, survive poorly but are able to stimulate the overgrowth of adjacent wild-type tissue. Experiments with mammalian cells show that reducing the level of RNA of the mammalian Uba1 ortholog, UBE1, also results in increased expression of specific growth factor genes. Our studies show that a reduction in E1 activity can promote tissue growth in a multicellular organism and raise the possibility that changes in E1 activity may occur during normal development or in cancer.