Transcriptional activation is a function of a """"""""coactivator code"""""""" in which multiple coactivators function in a combinatorial manner dictated by the context of the individual target gene and cell type. We have recently purified and characterized a novel transcriptional coactivator complex called ASCOM (for the ASC-2 complex), and this proposal focuses on the detailed molecular mechanisms by which ASCOM mediates transcriptional activation by nuclear receptors (NRs). The ASC-2 component of this complex is an NR coactivator protein independently isolated in this and at least five other laboratories. ASCOM also contains ALR-1/MLL2 (Trx/ALL-1/MLLl-related protein) and its splicing isoform ALR-2, ALR-like protein HALR (MLL3), ASH2, the Rb binding protein RBQ-3 and others. ALRol/ALR-2 and HALR exhibit histone methyltransferase (HMT) activity, and ASCOM represents the first NR coactivator complex associated with this important histone modification function. The central hypothesis of this proposal is that ASCOM, along with other complexes such as SRC/CBP, TRAP/DRIP, Swi/Snf and N-CoR/SMRT/HDAC, serves as a key mediator of transcriptional activation by NRs. Studies are proposed to test 1) the detailed biochemical function of different constituents of ASCOM during NR transcriptional activation and 2) the combinatorial coactivator code of ASCOM with other coactivators in NR transactivation, with an emphasis on Swi/Snf and CBP/p300. Our recent characterization of the biological functions of ASC-2 using transgenic mice has identified potential roles in many important processes, including metabolic regulation of lipid and cholesterol homeostasis. Gene-amplification as well as alterations of expression of ASC-2 and other ASCOM components in several human cancers also suggest a role in tumorigenesis. Thus, we believe that the studies proposed here will not only provide an important step toward fully understanding the molecular mechanisms by which NRs regulate transcription but could also lead to novel therapeutic approaches to the treatment of important human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064678-04
Application #
7190501
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$313,943
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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