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FEBS J. 2012 Jan;279(2):316-35. doi: 10.1111/j.1742-4658.2011.08426.x. Epub 2011 Dec 9.

Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma.

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1
Clinical Medical Research Institute of the First Affiliated Hospital, University of South China, Hengyang, China.

Abstract

Protein N-arginine methyltransferases (PRMTs) participate in a number of cellular processes, including cell growth, nuclear/cytoplasmic protein shuttling, differentiation, RNA splicing and post-transcriptional regulation. PRMT2 (also known as HRMT1L1) is clearly involved in lung function, the inflammatory response, apoptosis promotion, Wnt signaling and leptin signaling regulation through different mechanisms. In this study, we report the molecular and cell biological characterization of three novel PRMT2 splice variants isolated from breast cancer cells and referred to as PRMT2α, PRMT2β and PRMT2γ. Compared with the wild-type PRMT2, these variants lack different motifs and therefore generate distinct C-terminal domains. Confocal microscopy scanning revealed a distinct intracellular localization of PRMT2 variants, suggesting that the alternatively spliced C-terminus of PRMT2 can directly influence its subcellular localization. Our findings reveal that these variants are capable of binding to estrogen receptor alpha (ERα) both in vitro and in vivo, and the N-terminal regions of these variants contribute to ERα-PRMT2 interactions. Furthermore, these variants were proved to be able to enhance ERα-mediated transactivation activity. Luciferase reporter assays showed that PRMT2s could modulate promoter activities of the ERα-targeted genes of Snail and E-cadherin. In addition, PRMT2 silencing could enhance 17β-estradiol-induced proliferation by regulating E2F1 expression and E2F1-responsive genes in ERα-positive breast cancer cells. Real-time PCR and immunohistochemistry showed that overall PRMT2 expression was upregulated in breast cancer tissues and significantly associated with ERα positivity status both in breast cancer cell lines and breast cancer tissues. We speculate that PRMT2 and its splice variants may directly modulate ERα signaling and play a role in the progression of breast cancer.

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