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The gene encoding the splicing factor SF2/ASF is a proto-oncogene.

ABSTRACT: Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.

SUBMITTER: Karni R

PROVIDER: S-EPMC4595851 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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The gene encoding the splicing factor SF2/ASF is a proto-oncogene.

Karni Rotem R de Stanchina Elisa E Lowe Scott W SW Sinha Rahul R Mu David D Krainer Adrian R AR

Nature structural & molecular biology 20070218 3

Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of ...[more]

PMID: 17310252

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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

The gene encoding the splicing factor SF2/ASF is a proto-oncogene.

Publications

The gene encoding the splicing factor SF2/ASF is a proto-oncogene.

Similar Datasets

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