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대학원 세미나

05/30(목)16시 연사:김은지
작성자 관리자조회수 135날짜 2019.05.24
일시: 05월 30일(목) 4:00PM

장소 : 벤처관 711호

강사: 김은지(성균관대 교수)

제목: The regulatory mechanism of c-Fos/AP-1 activity by protein arginine methyltransferase 1 via autophagy

내용: Methylation is the important biochemical reaction to transfer a methyl group to substrates from methyl donor (S-adenosylmethionine; SAM; AdoMet). Methyltransferases catalyze this reaction and could have three types of substrates – DNA, RNA, and proteins. Methylation regulates gene expression, protein interaction, and enzymatic functions, and is concerned in various diseases. Of them, protein methylation is one of post-translational modifications (PTMs), can occur in histones (H2A, H2B, H3, H4) and non-histone proteins. Methylation of non-histone substrates have been studied in view of regulating cellular processes.
Protein arginine methyltransferase 1 (PRMT1) is belonged to type I PRMT family and generates monomethylarginine and dimethylarginine. PRMT1 is prevalent in mammalian and responsible for various functions in lymphocyte function, oxidative stress, inflammation, and cancer.
Activator protein 1 (AP-1) are noted transcriptional factors consisted of subunits – Fos proteins, Jun proteins, and activating transcription factors (ATFs). They form homodimer or heterodimer for activation and recognize the consensus AP-1 binding sequences. AP-1 modulates diverse cellular processes such as survival, differentiation, apoptosis, and development.
The expression of c-Fos is tightly regulated by numerous and complicated transcriptional and posttranscriptional mechanisms. In here, we found c-Fos is modulated by PRMT1 resulting in AP-1 activity. Under the ectopic expression of PRMT1 and c-Fos condition, AP-1 activity is synergistically increased. c-Fos and PRMT1 co-localized in cytosol, and this implied that c-Fos is non-histone substrate of PRMT1. To test the relation of methylation, we used PRMT1 dominant negative (DN) mutant for confirming synergistically induced AP-1 activity. The AP-1 activity was descended when PRMT1 dominant negative (DN) was transfected with c-Fos. In addition, the ectopic expression of c-Fos and PRMT1 increased the methylated arginines (mme-R and adme-R). To explore the c-Fos up-regulating mechanism, we performed RT-PCR, immunoprecipitation, and western blotting. The enhanced AP-1 activity was not affected by mitogen-associated protein kinases (MAPKs) or nuclear translocation of c-Fos. The expression level of c-Fos was not altered in transcriptional level, as well. However, performing cycloheximide (CHX) chase assay, the retention of c-Fos was prolonged by PRMT1. Moreover, c-Fos expression level was diminished in PRMT1 knockdown condition. c-Fos and PRMT1-mediated AP-1 activity was changed when autophagy inhibitor (3MA, LY290042) or inducer (rapamycin, rottlerin) were incubated with. Moreover, the formation of c-Fos puncta and lysosomes were downregulated by PRMT1. Therefore, PRMT1-mediated c-Fos methylation modulated c-Fos stability resulting in enhancement of c-Fos activity.
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