SRp20 is a proto-oncogene critical for cell proliferation and tumor induction and maintenance

Tumor Virus RNA Biology Laboratory, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
International journal of biological sciences (Impact Factor: 4.51). 12/2010; 6(7):806-26. DOI: 10.7150/ijbs.6.806
Source: PubMed


Tumor cells display a different profile of gene expression than their normal counterparts. Perturbations in the levels of cellular splicing factors can alter gene expression, potentially leading to tumorigenesis. We found that splicing factor SRp20 (SFRS3) is highly expressed in cancers. SRp20 regulated the expression of Forkhead box transcription factor M1 (FoxM1) and two of its transcriptional targets, PLK1 and Cdc25B, and controlled cell cycle progression and proliferation. Cancer cells with RNAi-mediated reduction of SRp20 expression exhibited G2/M arrest, growth retardation, and apoptosis. Increased SRp20 expression in rodent fibroblasts promoted immortal cell growth and transformation. More importantly, we found that SRp20 promoted tumor induction and the maintenance of tumor growth in nude mice and rendered immortal rodent fibroblasts tumorigenic. Collectively, these results suggest that increased SRp20 expression in tumor cells is a critical step for tumor initiation, progression, and maintenance.

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    • "Moreover, mutations in several components of the spliceosome were recently discovered in several cancers and are predicted to be driver mutations, providing further confirmation that splicing factors are indeed important players in cancer development (Papaemmanuil et al. 2011; Quesada et al. 2012). However, there is only limited information regarding the causal/functional role of alternative splicing regulators in cancer development and progression (Karni et al. 2007; Jia et al. 2010; Golan-Gerstl et al. 2011; Lefave et al. 2011; Anczukow et al. 2012; Cohen-Eliav et al. 2013). hnRNP proteins are abundant RNA-binding proteins expressed in most human tissues (Hanamura et al. 1998; Cooper et al. 2009). "
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    ABSTRACT: In recent years, it has become clear that splicing factors play a direct role in cancer development. We showed previously that splicing factors SRSF1, SRSF6, and hnRNP A2/B1 are up-regulated in several cancers and can act as oncogenes when up-regulated. Here we examined the role of splicing factors hnRNP A1/A1b and hnRNP A2/B1 in hepatocellular carcinoma (HCC). We show that the splicing factors hnRNP A1 and hnRNP A2 are up-regulated in HCC tumors derived from inflammation-induced liver cancer mouse model. Overexpression of hnRNP A1 or hnRNP A2, but not the splicing isoform hnRNP B1, induced tumor formation of immortalized liver progenitor cells, while knockdown of these proteins inhibited anchorage-independent growth and tumor growth of human liver cancer cell lines. In addition, we found that cells overexpressing hnRNP A2 showed constitutive activation of the Ras-MAPK-ERK pathway. In contrast, knockdown of hnRNP A2 inhibited the Ras-MAPK-ERK pathway and prevented ERK1/2 activation by EGF. Moreover, we found that hnRNP A2 regulates the splicing of A-Raf, reducing the production of a short dominant-negative isoform of A-Raf and elevating the full-length A-Raf transcript. Taken together, our data suggest that hnRNP A2 up-regulation in HCC induces an alternative splicing switch that down-regulates a dominant-negative isoform of A-Raf, leading to activation of the Raf-MEK-ERK pathway and cellular transformation.
    RNA 02/2014; 20(4). DOI:10.1261/rna.042259.113 · 4.94 Impact Factor
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    • "SRSF3 has been shown to regulate the splicing of fibronectin (de la Mata and Kornblihtt, 2006), itself (Jumaa and Nielsen, 1997), pyruvate kinase M (Christofk et al., 2008) and p53 (Tang et al., 2013). Knockout studies indicated that SRSF3 is essential for mouse development, hepatocyte differentiation and metabolic function, as well as tumor cell proliferation and maintenance (Sen et al., 2013; He et al., 2011; Jia et al., 2010; Jumaa et al., 1999). However, an understanding of the regulatory mechanisms of SRSF3 function is necessary to decipher the different effects caused by different modulators, such as caffeine. "
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    ABSTRACT: Caffeine causes a diverse range of pharmacological effects that are time- and concentration-dependent and reversible. The detailed mechanisms of caffeine in tumor suppression via tumor suppressor protein p53 remain unclear. The isoforms of p53 are physiological proteins that are expressed in normal cells and generated via alternative promoters, splicing sites and/or translational initiation sites. In this study, we investigated how caffeine modulated cell cycle arrest and apoptosis via the expression of various alternatively spliced p53 isoforms. Caffeine reduced p53α expression and induced the expression of p53β, which contains an alternatively spliced p53 C-terminus. In HeLa cells, the expression levels of many serine/arginine-rich splicing factors, including serine/arginine-rich splicing factors 2 and 3, were altered by caffeine. Serine/arginine-rich splicing factor 3 was a promising candidate for the serine/arginine-rich splicing factors responsible for the alternative splicing of p53 in response to caffeine treatment. In addition to p53-dependent functions, multiple target genes of serine/arginine-rich splicing factor 3 suggest that caffeine can regulate epithelial-mesenchymal-transition and hypoxic conditions to inhibit the survival of tumor cells. In summary, our data provide a new pathway of caffeine-modulated tumor suppression via the alternative splicing of the target genes of serine/arginine-rich splicing factor 3.
    The international journal of biochemistry & cell biology 12/2013; 47(1). DOI:10.1016/j.biocel.2013.12.004 · 4.05 Impact Factor
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    • "Alternative splicing plays a major role in cancer development and progression as many tumor suppressors and oncogenes are modulated by alternative splicing [10, 11]. However, the role of alternative splicing regulators in cancer development is mostly unknown, and only recently the first direct evidence for an oncogenic role of a splicing factor has been shown [9, 12–15]. "
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    ABSTRACT: Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.
    International Journal of Cell Biology 09/2013; 2013(11):568931. DOI:10.1155/2013/568931
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