Article

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: 4.37). 12/2010; 6(7):806-26.
Source: PubMed

ABSTRACT 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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Available from: J. Philip Mccoy, Jul 28, 2015
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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 · 4.62 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; DOI:10.1016/j.biocel.2013.12.004 · 4.24 Impact Factor
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    • "Moreover, when looking at SRp20 function in the splicing of human papillomavirus (HPV) RNA, Jia and collaborators found a remarkable increase in SRp20 expression in cervical cancer tissues [62]. This phenomenon is not limited to HPV-induced cancers; SRp20 is overexpressed also in lung, breast, stomach, skin, bladder, colon, liver, thyroid, and kidney tumor tissue, and in B-cell lymphoma cells [62]. SRp20 over-expression is required for ovarian cancer cell growth and maintenance of transformation properties [63] [64]. "
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    ABSTRACT: Alternative splicing in mRNA maturation has emerged as a major field of study also because of its implications in various diseases. The SR proteins play an important role in the regulation of this process. Evidence indicates that SRp20 (SFSR3), the smallest member of the SR protein family, is involved in numerous biological processes. Here we review the state-of-the-art of knowledge about the SR proteins, in particular SRp20, in terms of its function and misregulation in human diseases including cancer also in view of its potential as a therapeutic target.
    Biochemical and Biophysical Research Communications 05/2013; 436(1). DOI:10.1016/j.bbrc.2013.05.027 · 2.28 Impact Factor
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