Roles of Hippo and Ecdysone Receptor Signaling in the regulation of dronc
Authors: Karishma Gangwani 1; Amit Singh 1,2; Madhuri Kango-Singh 1,2
Affiliations: 1) Department of Biology, University of Dayton, Dayton OH; 2) Integrative Science and Engineering Center, University of Dayton
Keywords: a. caspases; p. transcriptional regulation
The Hippo pathway coordinately controls the essential growth regulatory processes of cell proliferation and death, and is required for regulating organ size in both flies and humans. Downregulation of Hippo signaling results in tissue overgrowth and tumorigenesis, whereas hyperactivation of Hippo signaling results in caspase-mediated cell death. Caspases are major regulators of apoptosis and suppression of caspase dependent apoptosis is often linked to aberrant growth. Further, JNK activation or hyperactivation of Hippo pathway by Mst1 (Drosophila Hippo) overexpression or YAP (Drosophila Yorkie, Yki) knockdown causes mitochondrial damage that induces Caspase-9 mediated apoptosis in cancer cell lines. Thus, caspases play a role in maintaining tissue homoeostasis and in diseases like cancer. Previously, we reported that the initiator caspase Drosophila Nedd-2 like caspase (dronc), Caspase-9 homolog, is a transcriptional target of the Hippo pathway in Drosophila. We showed that dronc transcription requires the growth inhibitory Hippo component Warts (Wts). Developmental apoptosis is controlled by small lipophilic hormones like ecdysone.Earlier studies have shown that dronc expression is regulated by the Ecdysone receptor (EcR) signaling pathway and an EcR regulatory element has been identified on the dronc promoter. Recently, Wts was shown to regulate Ecdysone production through Yki and the microRNA Bantam, suggesting a feedback mechanism involving Hippo and Ecdysone pathways. We found that depletion of Scalloped (Sd, TEAD in mammals) or Ecdysone receptor (EcR) or their corepressors resulted in derepression of dronc expression suggesting that dronc may be regulated by a default repression mechanism. Other preliminary data suggest that dronc regulation may involve cooperative interactions between Sd and EcR. Although an EcR binding site is mapped to the dronc promoter, the role of Sd has not been characterized. Using qRT-PCr based approaches we confirmed that dronc expression is regulated by Yki/Sd and EcR. Further, we identified a potential Sd site on the dronc promoter. Here, we present our work on the regulation of dronc by the Hippo and EcR signaling pathways, and its implications on development.