PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion.

RAS genes are frequently mutated in cancers, yet an effective treatment has not been developed, partly because of an incomplete understanding of signaling within Ras-related tumors. To address this, we performed a genetic screen in Drosophila, aiming to find mutations that cooperate with oncogenic Ras (RasV12) to induce tumor overgrowth and invasion. We identified fiery mountain (fmt), a regulatory subunit of the protein phosphatase 6 (PP6) complex, as a tumor suppressor that synergizes with RasV12 to drive c-Jun N-terminal kinase (JNK)-dependent tumor growth and invasiveness. We show that Fmt negatively regulates JNK upstream of dTAK1. We further demonstrate that disruption of PpV, the catalytic subunit of PP6, mimics fmt loss-of-function-induced tumorigenesis. Finally, Fmt synergizes with PpV to inhibit JNK-dependent tumor progression. Our data here further highlight the power of Drosophila as a model system to unravel molecular mechanisms that may be relevant to human cancer biology.

Evolution of Drosophila sex comb length illustrates the inextricable interplay between selection and variation.

In spite of the diversity of possible biological forms observed in nature, a limited range of morphospace is frequently occupied for a given trait. Several mechanisms have been proposed to explain this bias in the distribution of phenotypes including selection, drift, and developmental constraints. Despite extensive work on phenotypic bias, the underlying developmental mechanisms explaining why particular regions of morphological space remain unoccupied are poorly understood. To address this issue, we studied the sex comb, a group of modified bristles used in courtship that shows marked morphological diversity among Drosophila species. In many Drosophila species including Drosophila melanogaster, the sex comb rotates 90° to a vertical position during development. Here we analyze the effect of changing D. melanogaster sex comb length on the process of rotation. We find that artificial selection changes the number of bristles per comb without a proportional change in the space available for rotation. As a result, when increasing sex comb length, rather than displaying a similar straight vertical shape observed in other Drosophila species, long sex combs bend because rotation is blocked by a neighboring row of bristles. Our results show ways in which morphologies that would be favored by natural selection are apparently impossible to achieve developmentally. These findings highlight the potential role of development in modifying selectable variation in the evolution of Drosophila sex comb length.