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.
Highlights
Ubiquitination refers to the covalent attachment of the small protein ubiquitin to target proteins
Uba1 alleles were identified as autonomous suppressors of GMR-hid Expression of the pro-apoptotic gene hid [ known as Wrinkled (W) – FlyBase] under control of the eye-specific enhancer GMR (GMR-hid) causes a small eye phenotype due to excessive apoptosis (Fig. 1A) (Grether et al, 1995)
These results indicate that the suppressors of GMR-hid, D6, H33 and H42 encode new alleles of Uba1
Summary
Ubiquitination refers to the covalent attachment of the small protein ubiquitin to target proteins This modification usually targets ubiquitinated proteins for proteolytic degradation by the proteasome (reviewed by Glickman and Ciechanover, 2002; Pickart, 2004; Welchman et al, 2005). Non-traditional functions of ubiquitination, which do not target proteins for proteolysis, have been reported (Chen, 2005; Mukhopadhyay and Riezman, 2007; Welchman et al, 2005) In this regard, it is noteworthy that activated cell surface signaling receptors are ubiquitinated, usually
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