Dataset Information

Arginine methylation controls the subcellular localization and functions of the oncoprotein splicing factor SF2/ASF.

ABSTRACT: Alternative splicing and posttranslational modifications (PTMs) are major sources of protein diversity in eukaryotic proteomes. The SR protein SF2/ASF is an oncoprotein that functions in pre-mRNA splicing, with additional roles in other posttranscriptional and translational events. Functional studies of SR protein PTMs have focused exclusively on the reversible phosphorylation of Ser residues in the C-terminal RS domain. We confirmed that human SF2/ASF is methylated at residues R93, R97, and R109, which were identified in a global proteomic analysis of Arg methylation, and further investigated whether these methylated residues regulate the properties of SF2/ASF. We show that the three arginines additively control the subcellular localization of SF2/ASF and that both the positive charge and the methylation state are important. Mutations that block methylation and remove the positive charge result in the cytoplasmic accumulation of SF2/ASF. The consequent decrease in nuclear SF2/ASF levels prevents it from modulating the alternative splicing of target genes, results in higher translation stimulation, and abrogates the enhancement of nonsense-mediated mRNA decay. This study addresses the mechanisms by which Arg methylation and the associated positive charge regulate the activities of SF2/ASF and emphasizes the significance of localization control for an oncoprotein with multiple functions in different cellular compartments.

SUBMITTER: Sinha R

PROVIDER: S-EPMC2876523 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Arginine methylation controls the subcellular localization and functions of the oncoprotein splicing factor SF2/ASF.

Sinha Rahul R Allemand Eric E Zhang Zuo Z Karni Rotem R Myers Michael P MP Krainer Adrian R AR

Molecular and cellular biology 20100322 11

Alternative splicing and posttranslational modifications (PTMs) are major sources of protein diversity in eukaryotic proteomes. The SR protein SF2/ASF is an oncoprotein that functions in pre-mRNA splicing, with additional roles in other posttranscriptional and translational events. Functional studies of SR protein PTMs have focused exclusively on the reversible phosphorylation of Ser residues in the C-terminal RS domain. We confirmed that human SF2/ASF is methylated at residues R93, R97, and R10 ...[more]

PMID: 20308322

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Project description:Our previous study revealed that microRNA (miR) ?30c represents a potential tumor suppressor gene, the expression of which is associated with decreased oncogenic potential in prostate cancer (PCa) cell lines. However, the functional role and underlying mechanisms of miR?30c in PCa remain to be fully elucidated. Reverse transcription?quantitative polymerase chain reaction and immunohistochemical analysis were used to detect the expression levels of alternative splicing factor/splicing factor 2 (ASF/SF2) in PCa tissues. A luciferase reporter assay was used to investigate whether ASF/SF2 may be a direct target gene of miR?30c. In addition, the effects of miR?30c on the proliferation and apoptosis of PCa cell lines were examined, following transfection with miR?30c mimics. Furthermore, correlation analysis was performed to investigate the relationship between the expression of miR?30c and ASF/SF2 and various clinicopathological parameters of patients with PCa. The present results demonstrated that PCa tissues exhibited higher levels of alternative splicing factor/splicing factor 2 (ASF/SF2), compared with normal tissues. In addition, miR?30c was revealed to targete the 3'?untranslated region of the ASF/SF2 gene, causing a decrease in the mRNA and protein levels of ASF/SF2. Furthermore, miR?30c was reported to decrease cell proliferation, increase the percentage of cells in the G1 cell cycle phase, and promote apoptosis through the inhibition of ASF/SF2. Following correlation analysis using patient samples, the expression of ASF/SF2 was revealed to be tightly correlated with the pathological stage of PCa and biochemical recurrence (BCR). In addition, patients with PCa exhibiting low expression levels of miR?30c and high expression of ASF/SF2 had significantly lower rates of BCR?free survival. In conclusion, the present study suggested that the tumor suppressor miR?30c may be involved in PCa tumorigenesis, possibly via targeting ASF/SF2. The combined analysis of the expression of ASF/SF2 and miR?30c may be a valuable tool for early prediction of BCR in patients with PCa following radical prostatectomy.

Dataset Information

Arginine methylation controls the subcellular localization and functions of the oncoprotein splicing factor SF2/ASF.

Publications

Arginine methylation controls the subcellular localization and functions of the oncoprotein splicing factor SF2/ASF.

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