Abstract
BackgroundProtein arginine methyltransferase 5 (PRMT5) catalyzes the formation of symmetrical dimethylation of arginine residues in proteins. WD repeat domain 77 (WDR77), also known as p44, MEP50, or WD45, forms a stoichiometric complex with PRMT5. The PRMT5/p44 complex is required for cellular proliferation of lung and prostate epithelial cells during earlier stages of development and is re-activated during prostate and lung tumorigenesis. The molecular mechanisms by which PRMT5 and p44 promote cellular proliferation are unknown.MethodsExpression of PRMT5 and p44 in lung and prostate cancer cells was silenced and their target genes were identified. The regulation of target genes was validated in various cancer cells during lung development and tumorigenesis. Altered expression of target genes was achieved by ectopic cDNA expression and shRNA-mediated silencing.ResultsPRMT5 and p44 regulate expression of a specific set of genes encoding growth and anti-growth factors, including receptor tyrosine kinases and antiproliferative proteins. Genes whose expression was suppressed by PRMT5 and p44 encoded anti-growth factors and inhibited cell growth when ectopically expressed. In contrast, genes whose expression was enhanced by PRMT5 and p44 encoded growth factors and increased cell growth when expressed. Altered expression of target genes is associated with re-activation of PRMT5 and p44 during lung tumorigenesis.ConclusionsOur data provide the molecular basis by which PRMT5 and p44 regulate cell growth and lay a foundation for further investigation of their role in lung tumor initiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2632-3) contains supplementary material, which is available to authorized users.
Highlights
Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of symmetrical dimethylation of arginine residues in proteins
Silencing p44 expression did not affect PRMT5 mRNA expression and silencing PRMT5 slightly decreased (30 % reduction) p44 mRNA expression (Fig. 1a), which is statistically significant (p = 0.01755). These results are consistent with previous findings that p44 and PRMT5 proteins form a stoichiometric complex and co-exist in the cytoplasm [21]
We previously showed that ectopic expression of wild type FGFR3 or constitutively activated forms [FGFR3(S249C) and FGFR3 (Y375C)] of FGFR3 partially restored growth inhibition induced by PRMT5 silencing [20]
Summary
Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of symmetrical dimethylation of arginine residues in proteins. Protein arginine methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that catalyzes the symmetrical dimethylation of arginine residues within target proteins and has been implicated in diverse cellular and biological processes including transcriptional regulation [1,2,3], RNA metabolism [4, 5], ribosome biogenesis [6], Golgi apparatus structural maintenance [7], and cell cycle regulation [1]. Inhibition of PRMT5 activity redirected the response of PC12 cells to EGF from proliferation to differentiation [17]. Given these roles, PRMT5 is generally regarded to
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