The second messenger cAMP regulates the expression of distinct subsets of genes in a variety of cell functions. The goal of this proposal is to test the hypothesis that cAMP-mediated gene expression is regulated by a protein complex containing both co-activators and co-repressors. This model of gene activation is an extension of the current model of gene regulation that involves distinct co-activator and co- represser complexes, where the components of these complexes are discrete and mutually exclusive. Our preliminary data show that CBP, the co-activator of the CRE-binding protein CREB, forms a complex with co-repressor histone deacetylases (HDAC). Our model proposes that CREB, when phosphorylated by Protein Kinase A, recruits CBP, which in turn brings HDACs to the CREB/CBP complex. We have shown that CREB is acetylated within the cell, and that acetylation of CREB enhances CREB's transactivation activity. Because CBP is a known histone acetyltransferase(HAT) and is able to acetylate CREB, we hypothesize that acetylation of CREB is regulated by the complex consisting of CBP and HDACs. The experiments proposed in this application focus on understanding the mechanism by which acetylation of CREB regulates its activity and the role of HDACs in regulating CREB acetylation. The CREB/CBP system has served as a prototype to illustrate the effects of phosphorylation of transcription factors and their interaction with co-activators/co-repressors on regulation of gene expression. Knowledge and insights gained from the proposed studies will have important implications for understanding the role of acetylation of transcription factors in the regulation of gene transcription.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067102-05
Application #
7803670
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Margolis, Ronald N
Project Start
2006-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$257,748
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hada, Manila; Subramanian, Chitra; Andrews, Phillip C et al. (2016) Cytosolic Ku70 regulates Bax-mediated cell death. Tumour Biol 37:13903-13914
Hada, Manila; Kwok, Roland Ps (2014) Regulation of ku70-bax complex in cells. J Cell Death 7:11-3
Subramanian, Chitra; Hada, Manila; Opipari Jr, Anthony W et al. (2013) CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma. Mol Cancer Res 11:173-81
Subramanian, Chitra; Jarzembowski, Jason A; Halsey, Sonja M et al. (2011) CLU blocks HDACI-mediated killing of neuroblastoma. Tumour Biol 32:285-94
Subramanian, Chitra; Jarzembowski, Jason A; Opipari Jr, Anthony W et al. (2011) HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. Neoplasia 13:726-34
Mor-Vaknin, Nirit; Kappes, Ferdinand; Dick, Amalie E et al. (2011) DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum 63:556-67
Cui, Tracy Xiao; Kwok, Roland; Schwartz, Jessica (2008) Cooperative regulation of endogenous cAMP-response element binding protein and CCAAT/enhancer-binding protein beta in GH-stimulated c-fos expression. J Endocrinol 196:89-100