Protein arginine methylation is a prevalent posttranslational modification that is involved in a variety of processes including cell proliferation, signal transduction, protein trafficking, and transcription regulation. The mode of action of this family of protein arginine methyltransferase (PRMT) enzymes is largely unknown and many of their substrates have yet to be identified. Our long-term goal is to elucidate the biological function of coactivator-associated arginine methyltransferasel (CARM1), which binds the p160 family of coactivators and enhances transcriptional activation by nuclear receptors. An in vitro screen has been developed to identify novel arginine methyltransferase substrates. Using high-density protein arrays, we propose to identify new targets for PRMTs, map the methylated regions in these substrates, and establish the importance of this modification for substrate function. In parallel to these activities, gene-targeting methodology will be used to generate CARM1 mutant mice. Cells derived from mutant embryos will provide a genetically controlled tool for the in vivo analysis of putative substrates identified in the in vitro screen. In addition, the analysis of the CARM1 mutant mice/embryos will provide us with insight into the roles played by this enzyme in nuclear receptor signaling. The identification of new arginine methylated substrates would add to our understanding of transcriptional activation mediated by the nuclear hormone superfamily and may ultimately lead to the identification of a novel class of deregulated enzymes in disease states and new targets for drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062248-04
Application #
6905551
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Margolis, Ronald N
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$290,696
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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