We have elaborated a model of gene regulation (""""""""hit-and-run"""""""") based on the surprising finding that receptors and several of their coregulators exchange rapidly with regulatory elements in living cells. These proposals have led to a major paradigm shift in the field, and have resulted in invitations to a number of major forums (Keystone Transcription Meeting, 2006; Nuclear Receptors Stockholm, 2006; Cold Spring Harbor Chaperones, 2006; AACR 2006; Cold Spring Harbor Dynamics, 2006; ENDO 2006; FASEB Dynamics 2006; FEBS Symp Istanbul 2006; NICHD Symp 2006) . The model has been extended to describe interactions of the androgen receptor with chromatin templates in vivo and in vitro (Klokk et al, MCB in review, 2006), confirming that the general concept is broadly valid across the nuclear receptor superfamily.An outcome predicted by the """"""""hit-and-run"""""""" hypothesis is the potential modification of receptor activity during the process of hormone induction. We discovered (Qiu et al, Molecular Cell 2006) that HDAC1 is a coactivator for GR action, that the enzyme is acetylated after association with the glucocorticoid receptor, and that the deacetylase activity of the enzyme is strongly inhibited by the acetylation event. We also found that the acetylated form of the enzyme is associated with repressed chromatin while HDAC1 found in active chromatin fragments manifests low acetylation levels, and concluded that active acetylation of HDAC1 is a key event in the regulation of gene activity by nuclear receptors. This work presents a another major paradigm change in the field of gene regulation. HDAC's are currently viewed primarily as corepressors, serving in many complexes that are associated with silenced genes. Our work demonstrates that HDAC1 is a coactivator for GR mediated regulation, and introduces the novel concept of modification of HDAC activity by acetylation. This modification occurs progressively during hormone induction, and provides a new mechanistic basis for the phenomenon of promoter """"""""cycling,"""""""" recently described for several nuclear receptors. HDAC's are frequent members of complexes that are perturbed in cancer cells. Thus, this new concept will have important ramifications not only for mechanisms of gene regulation, but also in the broader field of cancer biology, and has attracted wide attention in the community.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005450-23
Application #
7337861
Study Section
(LRBG)
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
John, Sam; Johnson, Thomas A; Sung, Myong-Hee et al. (2009) Kinetic complexity of the global response to glucocorticoid receptor action. Endocrinology 150:1766-74
Biddie, Simon C; Hager, Gordon L (2009) Glucocorticoid receptor dynamics and gene regulation. Stress 12:193-205
Hakim, Ofir; John, Sam; Ling, Jian Qun et al. (2009) Glucocorticoid receptor activation of the Ciz1-Lcn2 locus by long range interactions. J Biol Chem 284:6048-52
George, Anuja A; Schiltz, R Louis; Hager, Gordon L (2009) Dynamic access of the glucocorticoid receptor to response elements in chromatin. Int J Biochem Cell Biol 41:214-24
Johnson, Thomas A; Elbi, Cem; Parekh, Bhavin S et al. (2008) Chromatin remodeling complexes interact dynamically with a glucocorticoid receptor-regulated promoter. Mol Biol Cell 19:3308-22
Sung, Myong-Hee; Bagain, Lorena; Chen, Zhong et al. (2008) Dynamic effect of bortezomib on nuclear factor-kappaB activity and gene expression in tumor cells. Mol Pharmacol 74:1215-22
Klokk, Tove I; Kurys, Piotr; Elbi, Cem et al. (2007) Ligand-specific dynamics of the androgen receptor at its response element in living cells. Mol Cell Biol 27:1823-43
Hager, Gordon L; Elbi, Cem; Johnson, Thomas A et al. (2006) Chromatin dynamics and the evolution of alternate promoter states. Chromosome Res 14:107-16
Qiu, Yi; Zhao, Yingming; Becker, Matthias et al. (2006) HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription. Mol Cell 22:669-79
Korkmaz, Ceren G; Korkmaz, Kemal S; Kurys, Piotr et al. (2005) Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer. Oncogene 24:4934-45

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