The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously.
Tom V Lee, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030; The Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Avenue, Houston, TX 77030
Tian Ding, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030; The Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Avenue, Houston, TX 77030
Zhihong Chen, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030
Vani Rajendran, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030
Heather Scherr, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030
Melinda Lackey, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030
Clare Bolduc, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030
Andreas Bergmann, The University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030; The Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Avenue, Houston, TX 77030
Abstract
Ubiquitination is an essential process regulating turnover of proteins for basic cellular processes such as the cell cycle and cell death (apoptosis). Ubiquitination is initiated by ubiquitin-activating enzymes (E1), which activate and transfer ubiquitin to ubiquitin-conjugating enzymes (E2). Conjugation of target proteins with ubiquitin is then mediated by ubiquitin ligases (E3). Ubiquitination has been well characterized using mammalian cell lines and yeast genetics. However, the consequences of partial or complete loss of ubiquitin conjugation in a multi-cellular organism are not well understood. Here, we report the characterization of Uba1, the only E1 in Drosophila. We found that weak and strong Uba1 alleles behave genetically differently with sometimes opposing phenotypes. Whereas weak Uba1 alleles protect cells from cell death, clones of strong Uba1 alleles are highly apoptotic. Strong Uba1 alleles cause cell cycle arrest which correlates with failure to reduce cyclin levels. Surprisingly, clones of strong Uba1 mutants stimulate neighboring wild-type tissue to undergo cell division in a non-autonomous manner giving rise to overgrowth phenotypes of the mosaic fly. We demonstrate that the non-autonomous overgrowth is caused by failure to downregulate Notch signaling in Uba1 mutant clones. In summary, the phenotypic analysis of Uba1 demonstrates that impaired ubiquitin conjugation has significant consequences for the organism, and may implicate Uba1 as a tumor suppressor gene.
