Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

Abstract

We targeted expression of human/¯y chimeric Bcr-Abl proteins to the developing central nervous system (CNS) and eye imaginal disc of Drosophila melanogaster. Neural expression of human/¯y chimeric P210 Bcr-Abl or P185 Bcr-Abl rescued abl mutant¯ies from pupal lethality, indicating that P210 and P185 Bcr-Abl can substitute functionally for Drosophila Abl during axonogenesis. However, increased levels of neurally expressed P210 or P185 Bcr-Abl but not Drosophila Abl produced CNS defects and lethality. Expression of P210 or P185 in the eye imaginal disc produced a dominant rough eye phenotype that was dependent on dosage of the transgene. Drosophila Enabled, previously identi®ed as a suppressor of the abl mutant phenotype and substrate for Drosophila Abl kinase, had markedly increased phosphotyrosine levels in Bcr-Abl expressing Drosophila, indicating that it is a substrate for Bcr-Abl as well. Drosophila, therefore, is a suitable model system to identify Bcr-Abl interactions important for signal transduction and oncogenesis.

Using Bcr-Abl to Examine Mechanisms by Which Abl Kinase Regulates Morphogenesis inDrosophila

“…Interestingly, each Bcr-Abl isoform can rescue abl mutants, suggesting that their signaling properties are not grossly altered. However, neural-specific expression of these oncogenes in a wild-type background disrupts CNS development, whereas neural-specific overexpression of wildtype Abl does not, suggesting that regulated kinase activity is important (Fogerty et al, 1999). Interestingly, some neuronal Bcr-Abl phenotypes resembled those of ena loss-offunction, and Ena phosphorylation was increased in Bcr-Abl expressing flies, consistent with Ena being a Bcr-Abl target.…”

“…Previous work demonstrated that regulated Abl activity is necessary for the correct development of the CNS and that CNS-specific expression of Bcr-Abl disrupts the CNS and results in embryonic lethality (Fogerty et al, 1999). Therefore, we assessed whether the embryonic lethality we observed using our GAL4 drivers was due to CNS disruption.…”

“…One way Abl may regulate Ena is by phosphorylation (Fogerty et al, 1999). The effects on embryogenesis of Abl and Bcr-Abl require kinase activity.…”

“…Fogerty et al (1999) generated transgenic Drosophila expressing p185 or p210 Bcr-Abl. In these, Bcr and the Nterminal Abl sequences are derived from the human oncogenes (these regions of Abl are highly similar in fly and human), whereas the C-terminal Abl tail is derived from Drosophila, maximizing the likelihood that the Bcr-Abl proteins would effectively interact with endogenous Drosophila regulators and targets.…”

Organization of F-Actin via Concerted Regulation of Kette by PTP61F and dAbl

“…All crosses were performed at 25°C unless otherwise indicated. The following strains were obtained from various sources: upstream activation sequence (UAS)-kette Myr /TM6B (6), UAS-dAbl/CyO (14), and UAS-dAbl K417N / CyO (14). To generate the PTP61F-RNA interference (RNAi) construct, the PTP61F DNA (coding sequence ϩ901 to ϩ1415) was cloned as an inverted repeat into the pWIZ vector (28).…”