Drosophila Tumor Model
Our interest has been focused on elucidating the complex role of the stress-inducible Jun-N-terminal kinase (JNK) pathway during malignant transformation using the Drosophila tumor model. By combining loss- and gain-of-function oncogenic events in visibly marked clonal tumors introduced into otherwise wild-type imaginal epithelium, we showed that the contribution of JNK signaling to tumor formation varied depending on the genotype of the tumor and also on the strength of the JNK signal. In essence, elevated JNK activity eradicated benign tumors by inducing apoptosis, but when apoptosis was suppressed in more malignant lesions, JNK stimulated aberrant growth in a non-autonomous manner (Uhlirova et al. 2005, Proc Natl Acad Sci USA). In highly malignant, invasive tumors, JNK had yet another function: it promoted cell motility and facilitated the spreading of tumor cells to secondary sites, ultimately killing the animal. This latter effect required the expression of a matrix metalloproteinase (MMP) in response to JNK signals (Uhlirova and Bohmann 2006, EMBO J).
Regulation of Epihelial Morphogenesis
Epithelial morphogenesis underlies tissue and organ formation during animal development as well as during tissue regeneration. The best-known examples in Drosophila include the embryonic dorsal closure, formation of the adult thorax, and wound healing. We are interested in less-well characterized process of the fly abdominal morphogenesis, which involves replacement of larval epidermal cells (LECs) with adult histoblasts during metamorphosis. We have implicated Drosophila Atf3 bZIP protein in abdominal morphogenesis. During the process of epithelial cell replacement, transcription of atf3 sharply declines. This down-regulation is critical, as sustained atf3 expression in the LECs leads to increased cell adhesion, thus preventing LECs extrusion and their replacement by histoblasts leaving the process of abdominal closure incomplete. Atf3 genetically interacts with Rho1 signaling. To elicit its effect, ectopic Atf3 specifically requires its binding partner dJun. Our data thus identify Atf3 as a new functional partner of Drosophila Jun during development (Sekyrova et al., 2010, Development, in press)..