Cyclic AMP stimulates the expression of numerous genes via the PK-A? mediated phosphorylation of CREB at Ser133. Ser133 phosphorylation in turn? regulates CREB activity by promoting complex formation with the signal? dependent co-activators CBP and P300. CBP/P300 have been proposed to? mediate transcriptional activation via their association with RNA? polymerase II, and via intrinsic histone acetyl transferase activities? that may counteract the repressive effects of promoter bound nucleosomes.? The proposed studies focus on the mechanism by which cellular signals? regulate complex formation between CREB and CBP, and on the mechanism by? which CBP-associated HAT activities promote expression of cAMP responsive? genes. The functional importance of contact residues in CREB and CBP for? transcriptional activation will be evaluated and additional phospho-? acceptor sites in CREB which regulate CREB:CBP complex formation will be? characterized. The functional importance of CBP-HAT activity for? transcriptional activation by phospho (Ser133) CREB will also be examined? by expressing wild-type and HAT defective CBP polypeptides in CBP -/-? cells. Finally, the mechanism by which histone deacetylase inhibitors? synergize with cAMP to promote accumulation of target gene transcripts? will be examined. Do cellular HAT activities stimulate assembly of the? transcriptional apparatus via chromatin remodeling? Based on recent? observations indicating a central role for CREB in learning and memory,? the information gained from these studies may contribute importantly to? our understanding of diseases which impair cognitive function.?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM037828-23
Application #
7152525
Study Section
Special Emphasis Panel (NSS)
Program Officer
Anderson, James J
Project Start
1986-12-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
23
Fiscal Year
2007
Total Cost
$632,506
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Wang, Biao; Goode, Jason; Best, Jennifer et al. (2008) The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila. Cell Metab 7:434-44
Shaw, Reuben J; Lamia, Katja A; Vasquez, Debbie et al. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642-6
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Conkright, Michael D; Canettieri, Gianluca; Screaton, Robert et al. (2003) TORCs: transducers of regulated CREB activity. Mol Cell 12:413-23
Jhala, Ulupi S; Canettieri, Gianluca; Screaton, Robert A et al. (2003) cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575-80
Long, F; Schipani, E; Asahara, H et al. (2001) The CREB family of activators is required for endochondral bone development. Development 128:541-50
Asahara, H; Santoso, B; Guzman, E et al. (2001) Chromatin-dependent cooperativity between constitutive and inducible activation domains in CREB. Mol Cell Biol 21:7892-900
Nakajima, T; Uchida, C; Anderson, S F et al. (1997) Analysis of a cAMP-responsive activator reveals a two-component mechanism for transcriptional induction via signal-dependent factors. Genes Dev 11:738-47
Nakajima, T; Uchida, C; Anderson, S F et al. (1997) RNA helicase A mediates association of CBP with RNA polymerase II. Cell 90:1107-12

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