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Journal of medicinal chemistry (1)
Molecular and Cellular Biology (1)
Cheng, Donghang (3)
Bedford, Mark T. (2)
Bedford, Marc T. (1)
Castellano, Sabrina (1)
Costi, Roberta (1)
Di Santo, Roberto (1)
Mai, Antonello (1)
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Tini, Marc (1)
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Novel 3,5-Bis(bromohydroxybenzylidene)piperidin-4-ones as Coactivator-associated Arginine Methyltransferase 1 Inhibitors: Enzyme Selectivity and Cellular Activity
Di Santo, Roberto
Bedford, Mark T.
Journal of medicinal chemistry
Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene) piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.
Xenoestrogens Regulate the Activity of Arginine Methyltransferases
Bedford, Mark T.
Arginine methylation is a common posttranslational modification that has been strongly implicated in transcriptional regulation. The arginine methyltransferases (PRMTs) were first reported as transcriptional coactivators for the estrogen and androgen receptors. Compounds that inhibit these enzymes will provide us with valuable tools for dissecting the roles of these enzymes in cells, and will possibly also have therapeutic applications. In order to identify such inhibitors of the PRMTs, we performed a high throughput screen using a small molecule library a number of years ago. We termed these compounds AMIs (arginine methyltransferase inhibitors). The majority of these inhibitors were polyphenols, and one in particular (AMI-18) shared additional features with a group of known xenoestrogens. We thus tested a panel of xenoestrogens and found that a number of them possess the ability to inhibit PRMT activity in vitro. These inhibitors primarily target CARM1, and include licochalcone A, kepone, benzyl 4-hydroxybenzoate, and tamoxifen. We developed a cell-based reporter system for CARM1 activity, and showed that tamoxifen (IC50=30 µM) inhibits this PRMT. The ability of these compounds to regulate the activity of transcriptional coactivators may be an unappreciated mechanism of action for xenoestrogens and may also explain the efficacy of high-dose tamoxifen treatment on estrogen receptor negative cancers.
PRMT1; CARM1; Arginine methylation; Xenoestrogens
The Activity and Stability of the Transcriptional Coactivator p/CIP/SRC-3 Are Regulated by CARM1-Dependent Methylation▿
Bedford, Marc T.
Molecular and Cellular Biology
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.
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