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Molecular and Cellular Biology, January 2007, p. 120-134, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00815-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Activity and Stability of the Transcriptional Coactivator p/CIP/SRC-3 Are Regulated by CARM1-Dependent Methylation{triangledown}

Hina Naeem,1,2 Donghang Cheng,4 Qingshi Zhao,1 Caroline Underhill,1 Marc Tini,2,3 Marc T. Bedford,4 and Joseph Torchia1,2*

Department of Oncology, London Regional Cancer Program,1 Department of Physiology and Pharmacology,2 Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada,3 University of Texas M. D. Anderson Cancer Center, Department of Carcinogenesis, Smithville, Texas 789574

Received 8 May 2006/ Returned for modification 18 June 2006/ Accepted 5 October 2006

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-3H]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.

* Corresponding author. Mailing address: Cancer Research Laboratories, London Regional Cancer Program, London, Ontario, Canada N6A 4L6. Phone: (519) 685-8692. Fax: (519) 685-8673. E-mail: jtorchia{at}uwo.ca.

{triangledown} Published ahead of print on 16 October 2006.

Molecular and Cellular Biology, January 2007, p. 120-134, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00815-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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