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.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Zhang, Qinghong; Wang, Su-Yan; Fleuriel, Capucine et al. (2007) Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Proc Natl Acad Sci U S A 104:829-33
Soderling, Scott H; Guire, Eric S; Kaech, Stefanie et al. (2007) A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. J Neurosci 27:355-65
Felmy, Felix (2007) Modulation of cargo release from dense core granules by size and actin network. Traffic 8:983-97
Zhang, Qinghong; Wang, Su-Yan; Nottke, Amanda C et al. (2006) Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci U S A 103:9029-33
Dodge-Kafka, Kimberly L; Langeberg, Lorene; Scott, John D (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins. Circ Res 98:993-1001
Wan, Lei; Almers, Wolfhard; Chen, Wenbiao (2005) Two ribeye genes in teleosts: the role of Ribeye in ribbon formation and bipolar cell development. J Neurosci 25:941-9
Pawson, Tony; Scott, John D (2005) Protein phosphorylation in signaling--50 years and counting. Trends Biochem Sci 30:286-90
Zhang, Qinghong; Nottke, Amanda; Goodman, Richard H (2005) Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis. Proc Natl Acad Sci U S A 102:2802-7
Jin, Jing; Smith, F Donelson; Stark, Chris et al. (2004) Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr Biol 14:1436-50
Taraska, Justin W; Almers, Wolfhard (2004) Bilayers merge even when exocytosis is transient. Proc Natl Acad Sci U S A 101:8780-5

Showing the most recent 10 out of 65 publications