Disease relevance of CARM1

• The staining intensity for CARM1 was significantly lower in benign prostate tissue specimens compared with PIN and prostatic adenocarcinoma specimens (P < 0.001) [1].
• Expression of CARM1 was not correlated with age, Gleason score sum, pathologic stage, lymph node metastasis, extraprostatic extension, surgical margin status, vascular invasion, or perineural invasion [1].
• METHODS: The expression of CARM1 in normal prostate epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma tissue was examined in 66 previously untreated patients with prostate carcinomas, as well as 12 patients with hormone-independent prostate carcinoma, using immunohistochemical methods [1].
• First, transfection studies demonstrated that overexpression of CARM1 wild-type protein resulted in increased Tax transactivation of the human T-cell lymphotropic virus type 1 (HTLV-1) long terminal repeat (LTR) [2].
• The identification of splicing factors that are methylated by CARM1, and protein-protein interactions that are regulated by CARM1, strongly implicates this enzyme in the regulation of alternative splicing and points toward its involvement in spinal muscular atrophy pathogenesis [3].

High impact information on CARM1

• Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53 [4].
• Deimination by PADI4 prevents arginine methylation by CARM1 [5].
• This modification appears on the estrogen-regulated pS2 promoter when the CARM1 methyltransferase is recruited during transcriptional activation [5].
• CARM1 can methylate histone H3 in vitro, and a mutation in the putative S-adenosylmethionine binding domain of CARM1 substantially reduced both methyltransferase and coactivator activities [6].
• Reciprocally, CARM1 stimulates the ATPase activity of BRG1, a key component in nucleosome remodeling [7].

Chemical compound and disease context of CARM1

• In the 12 patients with androgen-independent prostatic adenocarcinoma, the expression of CARM1 was significantly increased when compared with patients without previous hormonal treatment [1].

Biological context of CARM1

• We also provide functional evidence that arginine residues methylated by CARM1 play a critical role in GRIP-1-dependent transcriptional activation and in hormone-induced gene activation [8].
• Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression [9].
• Using wild-type CBP and a mutant of CBP lacking the CARM1-targeted arginine residues (R3A), we show that arginine methylation of CBP is required for IFN-gamma induction of MHC-II [10].
• Specific RNA interference reduced CARM1 expression as well as MHC-II expression [10].
• It also demonstrates the coordinated regulation of CIITA, CARM1, and the acetyltransferase cyclic-AMP response element binding (CREB)-binding protein (CBP) during this process [10].

Anatomical context of CARM1

• Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development [11].
• They also demonstrate for the first time that CARM1 occupancy, histone H3-R17 methylation, and citrullination are regulated at the promoters of inflammatory genes in monocytes, thereby suggesting a novel role for histone arginine modifications in inflammatory diseases [12].
• CARM1 regulates proliferation of PC12 cells by methylating HuD [13].

Associations of CARM1 with chemical compounds

• Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase [14].
• CONCLUSIONS: The authors found that overexpression of CARM1 was involved in the development of prostate carcinoma as well as androgen-independent prostate carcinoma [1].
• CARM1 might, therefore, represent a critical component of cAMP-dependent glucose metabolism in the liver [15].
• 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 [16].
• Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter [17].

Physical interactions of CARM1

• SRCAP exhibits synergistic activation with nuclear receptor coactivators and functionally interacts in vivo with glucocorticoid receptor-interacting protein-1 and coactivator-associated arginine methyltransferase-1 [18].
• Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex [19].
• Methylation of SRC-3 was localized to an arginine in its CARM1 binding region and correlated with decreased estrogen receptor alpha-mediated transcription, as seen with both cell-based and in vitro transcription assays [19].

Regulatory relationships of CARM1

• CARM1 synergizes with CIITA in activating MHC-II transcription and synergy is abrogated when an arginine methyltransferase-defective CARM1 mutant is used [10].
• Together, our data provide evidence that CARM1 enhances Tax transactivation of the HTLV-1 LTR through a direct interaction between CARM1 and Tax and this binding promotes methylation of histone H3 (R2, R17, and R26) [2].

Other interactions of CARM1

• Fli-I bound poorly to and did not cooperate with PRMT1, a CARM1-related protein arginine methyltransferase that also functions as an NR coactivator [20].
• HuR methylation increased in cells that overexpressed CARM1 [14].
• Methylation of histone H3 and possibly other proteins in the transcription initiation complex by CARM1 occurs along with acetylation of histones and other proteins by CBP and p300 to help remodel chromatin structure and recruit RNA polymerase II [21].
• Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status [1].
• Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression [10].

Analytical, diagnostic and therapeutic context of CARM1

• Using high density protein arrays, we have previously identified in vitro substrates for CARM1 [11].
• Immunoprecipitation with anti-p65 antibody revealed that CARM1 physically interacts with NF-kappaB p65 [12].
• Finally, chromatin immunoprecipitation analysis of the activated HTLV-1 LTR promoter showed the association of CARM1 and methylated histone H3 with the template DNA [2].
• Chromatin immunoprecipitation assays and immunofluorescence studies indicated that CARM1 and the CARM1-methylated form of histone H3 specifically associated with a large tandem array of MMTV promoters in a hormone-dependent manner [17].

References