The transcriptional response to tumorigenic polarity loss. Brandon D. Bunker¹, Anne-Kathrin Classen², Tittu T. Nellimoottil³, David Bilder¹. 1) Molecular and Cell Biology, University of California-Berkeley, Berkeley, CA 94720; 2) Biology II, Ludwig-Maximilians-University, Munich, D-82152 Germany; 3) Biological Sciences, University of Southern California, Los Angeles, CA 90033.

   Genetic screens for growth regulators have identified scribble (scrib), lethal giant larvae (lgl), and discs large (dlg) as a distinctive class of tumor suppressor genes whose basic cellular activity is to control epithelial polarity. However, the mechanisms coupling polarity disruption to the transcriptional changes driving tumorigenesis remain unclear. To address this question, we analyzed the transcriptomes of wing imaginal discs mutant for scrib and dlg. Changes in gene expression highlighted several features associated with neoplastic transformation. Prominent amongst these was the transcriptional upregulation of the Unpaired (upd) family of JAK-STAT ligands; subsequent functional experiments demonstrated that increased JAK-STAT signaling promotes dlg overgrowth. To investigate the molecular pathways activating transcription upon polarity loss, we analyzed upd3 gene regulatory elements. While previous work has identified a role for the Jun kinase (JNK) pathway in JAK-STAT activation upon polarity loss, our experiments uncovered a polarity-responsive region in the upd3 enhancer whose activation was JNK-independent. In contrast, we found that the apical polarity regulator atypical protein kinase C (aPKC) is sufficient to drive expression of this element in a JNK-independent manner. Taken together, these results reveal how different signaling inputs elicited by polarity disruption integrate to drive mitogenic gene expression.