The research program described here aims at a full understanding of gene regulation by the steroid hormone ecdysone. Ecdysone regulates the development of insects and induces metamorphosis. Eip28/29, and ecdysone-responsive gene from Drosophila, is a model for steroid- regulated genes. Like other examples of such genes, its activity can be either elevated or depressed by the hormone, depending upon tissue and developmental stage. For example, Eip28/29 is induced by ecdysone in blood cells (and in some cell lines), but at the same time it is repressed by ecdysone in the epidermis and fat body. The regulatory DNA sequences (ecdysone response elements--EcREs--and other cis-acting elements) responsible for these diverse responses are distinct. The goal of the experiments proposed here is to understand ecdysone regulation in each class of tissue by identifying the relevant regulatory sequences, identifying and cloning the proteins that interact with them, and testing possible regulatory mechanisms. Mutant regulatory regions will be tested in cultured cells (by transient expression) and in the epidermis (by P element-mediated transformation of flies). Proteins which interact with these sequences will be identified by their binding to specific DNA sequences and/or by their activities in modifying transcription in vitro. Such proteins should include a variety of transcription factors, including factors which affect either EcRE-receptor binding or receptor activity after binding. They should also include transcription factors with more general functions. Since signal transduction by ecdysone is extremely similar to that of the vertebrate steroids, the results should provide useful insights into the activities of the more medically relevant vertebrate hormones. Similarly, transcription factors identified in Drosophila are likely to play important roles in gene regulation in other organisms.

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National Institute of General Medical Sciences (NIGMS)
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Molecular Biology Study Section (MBY)
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Indiana University Bloomington
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Cherbas, Lucy; Hu, Xiao; Zhimulev, Igor et al. (2003) EcR isoforms in Drosophila: testing tissue-specific requirements by targeted blockade and rescue. Development 130:271-84
Hu, Xiao; Cherbas, Lucy; Cherbas, Peter (2003) Transcription activation by the ecdysone receptor (EcR/USP): identification of activation functions. Mol Endocrinol 17:716-31
Riddiford, L M; Cherbas, P; Truman, J W (2000) Ecdysone receptors and their biological actions. Vitam Horm 60:Jan-73
Cherbas, L; Cherbas, P (1997) ""Parahomologous"" gene targeting in Drosophila cells: an efficient, homology-dependent pathway of illegitimate recombination near a target site. Genetics 145:349-58
Swevers, L; Cherbas, L; Cherbas, P et al. (1996) Bombyx EcR (BmEcR) and Bombyx USP (BmCF1) combine to form a functional ecdysone receptor. Insect Biochem Mol Biol 26:217-21
Segal, D; Cherbas, L; Cherbas, P (1996) Genetic transformation of Drosophila cells in culture by P element-mediated transposition. Somat Cell Mol Genet 22:159-65
Andres, A J; Cherbas, P (1994) Tissue-specific regulation by ecdysone: distinct patterns of Eip28/29 expression are controlled by different ecdysone response elements. Dev Genet 15:320-31
Cherbas, P (1993) The IVth Karlson Lecture: ecdysone-responsive genes. Insect Biochem Mol Biol 23:3-11
Cherbas, L; Cherbas, P (1993) The arthropod initiator: the capsite consensus plays an important role in transcription. Insect Biochem Mol Biol 23:81-90
Andres, A J; Cherbas, P (1992) Tissue-specific ecdysone responses: regulation of the Drosophila genes Eip28/29 and Eip40 during larval development. Development 116:865-76

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