The pathway of gene regulation linking hormone receptor activation to the induction of cAMP-regulated endocrine genes is one of the best characterized transcriptional pathways. A key process in this pathway is the phosphorylation of the transcription factor CREB by the catalytic subunit of the cAMP-dependent protein kinase A (PKA). The principal investigator has proposed that this phosphorylation event allows CREB to recruit a co-activator protein, CBP, which is responsible for transcriptional activation. This model was recently extended by the finding from another laboratory that phosphorylated c-jun also functions through CBP. These findings, along with the newly appreciated relationship between CBP and the adenovirus E1A-associated protein p3OO, may explain how E1A inhibits the expression of cAMP- and phorbol ester- regulated genes and leads to cellular immortalization.
The specific aims of this proposal are to: l) Rigorously determine whether c-jun phosphorylated by jun kinase interacts with the CREB-binding domains of CBP and p3OO. Fluorescence anisotropy measurements will be performed to compare the binding of phosphorylated c-jun and CREB to CBP and p3OO under equilibrium, solution- phase conditions to test whether competition for CBP/p300 binding explains the phenomenon of CREB/jun """"""""squelching."""""""" 2) Test whether HTLV-1 Tax stimulates cAMP-mediated gene expression by augmenting the association of phosphoCREB and CREM with CBP. 3) Determine whether tissue- and developmental stage-specific Ets-domain proteins that interact with the """"""""activation"""""""" domains of CBP and p3OO contribute to the process of synergistic signaling. 4) Determine the role of the CBP/p300 bromodomain and the proteins that bind to this region.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050014-04
Application #
2749552
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1995-08-01
Project End
1999-07-31
Budget Start
1998-08-11
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239