PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has selective antitumor activity. Although TNF-α-induced intracellular signaling pathways have been well studied, TRAIL signaling is not fully understood. Here, we identified a novel TRAIL receptor-binding protein, protein arginine methyltransferase 5 (PRMT5), as a result of proteomic screening. PRMT5 selectively interacted with death receptor 4 and death receptor 5 but not with TNF receptor 1 or Fas. PRMT5 gene silencing sensitized various cancer cells to TRAIL without affecting TRAIL resistance in nontransformed cells. PRMT5 contributed to TRAIL-induced activation of inhibitor of κB kinase (IKK) and nuclear factor-κB (NF-κB), leading to induction of several NF-κB target genes. Although IKK inhibition increased sensitivity to both TRAIL and TNF-α, PRMT5 knockdown potentiated TRAIL-mediated cytotoxicity alone. PRMT5 had no effect on TNF-α-mediated NF-κB signaling. These results show the selectivity of PRMT5 for TRAIL signaling. The PRMT5 small interfering RNA-mediated susceptibility to TRAIL was rescued by ectopic expression of active IKKβ, confirming the involvement of PRMT5 in TRAIL resistance by activating the NF-κB pathway. Collectively, our findings suggest the therapeutic potential of PRMT5 in TRAIL-based cancer treatments. (Mol Cancer Res 2009;7(4):557-69)

Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer

“…PRMT5 is a type II PRMT that catalyses the transfer of methyl groups from S-adenosyl methionine to the arginine residues of histones or non-histone proteins and is involved in numerous cellular processes (19,30). Because PRMT5 possesses multiple cellular functions, it is an important determinant of oncological properties of various malignancies (12)(13)(14)17,18). In the present study, analyses of the expression levels of PRMT5 and their effects on the phenotypes of GC cell lines, patient characteristics and outcomes were performed to assess the potential of PRMT5 as a novel biomarker and therapeutic target for patients with GC.…”

“…Protein arginine methyltransferase 5 (PRMT5) catalyses the symmetrical dimethylation of arginine residues of histone and non-histone substrates (12)(13)(14). Because PRMT5 is implicated in diverse cellular and biological processes such as transcriptional regulation, RNA metabolism, ribosome biogenesis, Golgi apparatus homeostasis and cell cycle regulation, PRMT5 is generating increased interest in the field of cancer research (12,15,16).…”

“…Because PRMT5 is implicated in diverse cellular and biological processes such as transcriptional regulation, RNA metabolism, ribosome biogenesis, Golgi apparatus homeostasis and cell cycle regulation, PRMT5 is generating increased interest in the field of cancer research (12,15,16). For example, PRMT5 is expressed at higher levels compared with normal tissues in leukemias, lymphomas and gliomas as well as in ovarian, breast, prostate and lung cancers (13,14,(17)(18)(19)(20).…”

Protein Arginine Methyltransferase 5 (PRMT5) Signaling Suppresses Protein Kinase Cδ- and p38δ-dependent Signaling and Keratinocyte Differentiation

“…PRMT5 modulates enhanced GFR-mediated ERK activation (33) and is required for p53 expression and induction of p53 targets (34). PRMT5 also binds to death receptor 4 (35). An important study shows that PRMT1 modulates p38 MAPK regulation of differentiation in megakaryocytes (36).…”

PRMT5 suppresses DR4-mediated CCL20 release via NF-κB pathway

“…Therefore, PRMT5 plays an important role in regulating cell proliferation. PRMT5 can also affect the release of cytokines through epigenetic regulation [7].…”