The current proposal takes a fresh look at trying to understand how a single DNA element, the cyclic AMP-regulated enhancer (CRE), participates in the diverse regulation element in the somatostatin and PEPCK genes, the CRE has been found to contribute to the regulation of dozens of cellular, viral, and even plant genes. Even within a single gene, the CRE appears to be involved in the response to multiple regulatory pathways. Thus, gene regulation through CRE sequences has become much more complicated than originally envisioned. The diversity of proteins that interact with the CRE is now recognized to extend far beyond the originally-described CRE- binding factor known as CREB. It has not been possible to determine which of these factors interact with particular CRE sequences or, in many cases, which factors participate in particular regulatory pathways. Unfortunately, the components of CRE-mediated gene regulation may prove to be too complex to be dissected in mammalian systems. The potential to use genetics to dissect the components of complex regulatory systems led us to search for CRE-binding proteins in Drosophila. The Drosophila system not only allows us to determine whether a specific CRE-binding protein binds to a particular gene, but also allows us to ablate individual CRE-binding proteins and measure the effects of these manipulations on expression of specific target genes. Characterization of the regulatory regions of the Drosophila CREB genes should allow us to replace one subtype of CREB with another and assay the consequences of this switch in intact animals. Finally, we should be able to use genetic manipulations to identify enhancers or suppressors of individual CRE- binding transcription factors and thus characterize upstream and downstream components of CRE-regulated gene expression. Because specific mutations within the Drosophila CREB-like genes can be generated, it will be possible to describe the interactions among the different factors and assign specific functions to each component of the CRE-regulatory system. It is reasonable to assume that such regulatory themes will be conserved between flies and man and that the insights gained from our studies will aid the understanding of the mammalian CREB functions.

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