The activity and stability of the transcriptional coactivator p/ CIP/ SRC-3 are regulated by CARM1-dependent methylation.
The transcriptional coactivator p/CIP(SRC-3/ AIB1/ ACTR/ RAC3) binds liganded nuclear hormone receptors and facilitates transcription by directly recruiting accessory factors such as acetyltransferase CBP/p300 and the coactivator arginine methyltransferase CARM1. In the present study, we have established that recombinant p/ CIP (p300/ CBP interacting protein) is robustly methylated by CARM1 in vitro but not by other protein arginine methyltransferase family members. Metabolic labeling of MCF-7 breast cancer cells with S-adenosyl-L-[methyl-(3)H]methionine and immunoblotting using dimethyl arginine-specific antibodies demonstrated that p/ CIP is specifically methylated in intact cells. In addition, methylation of full-length p/ CIP is not supported by extracts derived from CARM1(-/-) mouse embryo fibroblasts, indicating that CARM1 is required for p/ CIP methylation. Using mass spectrometry, we have identified three CARM1-dependent methylation sites located in a glutamine-rich region within the carboxy terminus of p/ CIP which are conserved among all steroid receptor coactivator proteins. These results were confirmed by in vitro methylation of p/ CIP using carboxy-terminal truncation mutants and synthetic peptides as substrates for CARM1. Analysis of methylation site mutants revealed that arginine methylation causes an increase in full-length p/ CIP turnover as a result of enhanced degradation. Additionally, methylation negatively impacts transcription via a second mechanism by impairing the ability of p/ CIP to associate with CBP. Collectively, our data highlight coactivator methylation as an important regulatory mechanism in hormonal signaling.[1]References
- The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation. Naeem, H., Cheng, D., Zhao, Q., Underhill, C., Tini, M., Bedford, M.T., Torchia, J. Mol. Cell. Biol. (2007) [Pubmed]
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