Alterations in Expression Pattern of Splicing Factors in Epithelial Ovarian Cancer and its Clinical Impact

Iborra, Séverine; Hirschfeld, Marc; Jaeger, Markus; Hausen, Axel zur; Braicu, Elena Ioana; Sehouli, Jalid; Gitsch, G.; Stickeler, Elmar

doi:10.1097/igc.0b013e31829783e3

Cited by 31 publications

(25 citation statements)

References 19 publications

(18 reference statements)

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“…In mice, SRSF3 expression is essential for early embryogenesis, liver differentiation, and metabolic function (Jumaa et al 1999;Sen et al 2013). SRSF3 was recently identified as a protooncogene important for cell viability and growth (Jia et al 2010), and increased expression of SRSF3 is common in many types of human cancers (Jia et al 2010;He et al 2011;Corbo et al 2012;Iborra et al 2013). SRSF3 overexpression leads to cell transformation, tumor induction, and the maintenance of tumor growth (Jia et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma–associated herpesvirus ORF57 protein is required for RNA splicing

Majerčiak

et al. 2014

RNA

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Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 is a multifunctional post-transcriptional regulator essential for viral gene expression during KSHV lytic infection. ORF57 requires interactions with various cellular proteins for its function. Here, we identified serine/arginine-rich splicing factor 3 (SRSF3, formerly known as SRp20) as a cellular cofactor involved in ORF57-mediated splicing of KSHV K8β RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits K8β splicing. Knockdown of SRSF3 promotes K8β splicing, mimicking the effect of ORF57. The N-terminal half of ORF57 binds to the RNA recognition motif of SRSF3, which prevents SRSF3 from associating with the K8β intron RNA and therefore attenuates the suppressive effect of SRSF3 on K8β splicing. ORF57 also promotes splicing of heterologous non-KSHV transcripts that are negatively regulated by SRSF3, indicating that the effect of ORF57 on SRSF3 activity is independent of RNA target. SPEN proteins, previously identified as ORF57-interacting partners, suppress ORF57 splicing activity by displacing ORF57 from SRSF3-RNA complexes. In summary, we have identified modulation of SRSF3 activity as the molecular mechanism by which ORF57 promotes RNA splicing.

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Section: Introductionmentioning

confidence: 99%

Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma–associated herpesvirus ORF57 protein is required for RNA splicing

Majerčiak

et al. 2014

RNA

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“…TRA2β is up-regulated in tumors of the lung, ovary, cervix, colon, and breast (Fischer et al 2004;Watermann et al 2006;Iborra et al 2013). TRA2β up-regulation is associated with invasive breast cancer, and medium to high TRA2β expression is associated with poor prognosis in cervical cancer (Fischer et al 2004;Watermann et al 2006;Iborra et al 2013). Although TRA2β expression is associated with cancer cell survival, its contribution to disease progression is still poorly understood.…”

Section: Tra2β-transformer 2β Homolog (Drosophila)mentioning

confidence: 99%

“…SRSF1 is frequently overexpressed in many solid tumors, relative to their respective normal controls, including tumors of the breast (13%), colon (25%), lung (25%), as well as thyroid, small intestine, kidney, and ovarian tumors (Watermann et al 2006;Karni et al 2007;Anczukow et al 2012Anczukow et al , 2015Das et al 2012;Iborra et al 2013). Modest SRSF1 overexpression is sufficient to promote transformation of immortal rodent fibroblasts (Karni et al 2007), as well as human mammary epithelial cells in vitro and in vivo ( Fig.…”

Section: Srsf1-serine/arginine-rich Splicing Factormentioning

confidence: 99%

“…SRSF3 is an essential gene: Srsf3 knockout (KO) in mice results in an early lethal phenotype, suggesting a fundamental and nonredundant function for each SR protein in embryonic development (Jumaa et al 1999). In human tumors, SRSF3 is overexpressed in ovarian, cervical, lung, colon, breast, stomach, skin, bladder, thyroid, liver, and kidney cancer (He et al 2004(He et al , 2011Jia et al 2010;Iborra et al 2013), at least in part due to copy-number changes in Chr. 6p21.…”

Section: Srsf3-serine/arginine-rich Splicing Factormentioning

confidence: 99%

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Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

227

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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“…Although the molecular mechanism responsible for tumorrelated alternative splicing events is not comprehensively understood, changes in the expression level of splicing factors correlate with alternative splicing events in malignant tumor cells (Cohen-Eliav et al 2013;Iborra et al 2013). Serine-arginine (SR) proteins comprise a family of splicing factors that exert influence on the utilization of the splice site by interacting with the cis-elements of candidate pre-mRNAs and trans-splicing factors (Wang et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events

Lin

Tarn

et al. 2014

RNA

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Imbalanced splicing of premessenger RNA is typical of tumorous malignancies, and the regulatory mechanisms involved in several tumorigenesis-associated splicing events are identified. Elevated expression of serine-arginine protein kinase 1 (SRPK1) may participate in the pathway responsible for the dysregulation of splicing events in malignant tumor cells. In this study, we observed a correlation between the cytoplasmic accumulation of RNA-binding motif protein 4 (RBM4) and up-regulated SRPK1 in breast cancer cells. The production of the IR-B and MCL-1 S transcripts was induced separately by the overexpression of RBM4 and SRPK1 gene silencing. Overexpressed RBM4 simultaneously bound to the CU-rich elements within the MCL-1 exon2 and the downstream intron, which subsequently facilitated the exclusion of the regulated exon. Breast cancer cells are deprived of apoptotic resistance through the RBM4-mediated up-regulation of the IR-B and MCL-1 S transcripts. These findings suggest that the splicing events regulated by the SRPK1-RMB4 network may contribute to tumorigenesis through altered sensitivity to apoptotic signals in breast cancer cells.

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Alterations in Expression Pattern of Splicing Factors in Epithelial Ovarian Cancer and its Clinical Impact

Cited by 31 publications

References 19 publications

Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma–associated herpesvirus ORF57 protein is required for RNA splicing

Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma–associated herpesvirus ORF57 protein is required for RNA splicing

Splicing-factor alterations in cancers

Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events

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