Insight into the role of alternative splicing within the RBM10v1 exon 10 tandem donor site

Tessier, Sarah; Loiselle, Julie J.; McBain, Anne; Pullen, Celine; Koenderink, Benjamin W; Roy, Justin G.; Sutherland, Leslie C.

doi:10.1186/s13104-015-0983-5

Cited by 12 publications

(17 citation statements)

References 29 publications

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“…RBM10 was upregulated in lung adenocarcinoma cells and lung adenocarcinoma tissues, compared with normal lung cells and normal lung tissues adjacent to the tumor. Our findings are consistent with other findings (21,22,25,26). We also demonstrated that RBM10 was mainly expressed in the cell nucleus, and to the best of our knowledge, this is the first time this has been reported.…”

Section: Discussionsupporting

confidence: 94%

“…At present, there are different opinions about whether RBM10 is a cancer-suppressor gene or an oncogene. In previous studies, opposing results have been found (22,26,38); however, the current study can partly explain the contradictory findings. RBM10 has three variants (RBM10v1, RBM10v2 and RBM10v3), with RBM10v1 and RBM10v2 playing the leading roles (11,23,39).…”

Section: Discussioncontrasting

confidence: 89%

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Functional role of RBM10 in lung adenocarcinoma proliferation

et al. 2018

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Lung cancer is one of the most common causes of morbidity and mortality among malignant tumors worldwide. The poor prognosis of patients with lung adenocarcinomas is primarily due to its strong ability to invade and metastasize. Recent research has indicated that RNA-binding protein 10 (RBM10) is mutated in lung adenocarcinoma, and is closely associated with tumor proliferation and apoptosis; however, the precise role of RBM10 in lung adenocarcinoma remains unclear. Our preliminary experiments (unpublished data) revealed that RBM10 expression was upregulated in lung adenocarcinoma cell lines and tissues. In this study, we first detected the protein expression level of RBM10 in lung adenocarcinoma cells and tissues, and we then examined the effects of RBM10 overexpression and downregulation (via small interfering RNA) on the proliferation and apoptosis of stable lung adenocarcinoma cells, along with its possible mechanisms of action. We also used clinical samples of lung adenocarcinomas to verify our results. We found that RBM10 protein was overexpressed in lung adenocarcinoma cells and tissues, and it reduced p53 expression (as detected by immunofluorescence assay and western blot analysis) in A549 cells and inhibited apoptosis (as shown by flow cytometric assay). RBM10 also promoted cell growth and proliferation in vitro and increased cell migration in a cell wound scratch assay. Furthermore, we found that RBM10 activated key proliferative signaling pathways [such as the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-AKT pathways] and inhibited apoptotic pathways. In addition, we demonstrated that a high expression of RBM10 protein in patient tissue samples was associated with a shorter overall survival time and a poor prognosis. On the whole, the findings of this study indicate that RBM10 may function as an oncogene in lung cancer, and may thus prove to be a novel therapeutic target for the prophylaxis and treatment of lung adenocarcinomas.

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Section: Discussionsupporting

confidence: 94%

Section: Discussioncontrasting

confidence: 89%

Functional role of RBM10 in lung adenocarcinoma proliferation

et al. 2018

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“…The single valine residue that differentiates the two RBM10v1 variants, as well as the two RBM10v2 variants, occurs within the second RNA Recognition Motif (RRM) of RBM10. The presence or absence of this valine residue can influence the α-helical structure of this RRM domain, and could thus influence RBM10’s binding targets [ 13 , 14 ]. Although the functional implications of this modification have yet to be tested, the level of binding specificity exhibited by RBM5 suggests that (1) the presence or absence of this valine residue modifies RBM10’s structure sufficiently for proteins (at least RBM5) to be able to distinguish between variants, and (2) RBM10 splice variants have specific, potentially opposing, roles in the cell, and thus require specific regulation.…”

Section: Discussionmentioning

confidence: 99%

“…RBM10 has two main alternative splice variants termed RBM10 variant 1 ( RBM10v1 ) and RBM10 variant 2 ( RBM10v2 ) [ 10 – 12 ]. Each main RBM10 splice variant also codes for alternative isoforms with or without the addition of one valine residue ( Fig 1 ) [ 13 ]. Structurally, RBM10v2 and RBM5 share 53% homology at the amino acid level [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

RBM10 promotes transformation-associated processes in small cell lung cancer and is directly regulated by RBM5

2017

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Lung cancers are the leading cause of cancer-related deaths worldwide, with small cell lung cancer (SCLC) being the most aggressive type. At the time of diagnosis, SCLC has usually already metastasized, and an astonishing 95% of patients eventually succumb to the disease. This highlights the need for more effective SCLC screening and treatment options. Interestingly, the earliest and most frequent genetic alteration associated with lung cancers involves a lesion in the region to which the RNA binding protein RBM5 maps. We have recently shown that a decrease in RBM5 expression may be a key step in SCLC development, as RBM5 regulated many transformation-associated processes in SCLC cells. RBM5 is structurally and functionally similar to another RNA binding protein, RBM10. Both proteins have tumor-suppressor properties in a variety of cancer cell lines, and it has been suggested that RBM5 expression can influence RBM10. Due to their similarities, and the recent evidence that RBM10 is mutated in up to 21% of lung cancers, we hypothesized that RBM10 would share RBM5’s tumor-suppressor properties in SCLC. Using transcriptome analysis and functional assays, we show, however, that RBM10’s function was opposite to what we hypothesized; in the endogenously RBM5-null GLC20 SCLC cell line, RBM10 actually promoted cell proliferation and other transformation-associated processes. Using RNA immunoprecipitation followed by next generation sequencing (RIP-Seq) and Western blotting, we demonstrate that RBM5 post-transcriptionally regulated RBM10 expression via direct interaction with specific RBM10 splice variants. We propose a working model describing the impact of this interaction on cellular processes. Our results provide evidence that RBM10 expression, in RBM5-null tumors, may contribute to tumor growth and metastasis. Measurement of both RBM10 and RBM5 expression in clinical samples may therefore hold prognostic and/or potentially predictive value.

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“…Functionally, overexpressed RBM10 causes apoptosis, and low levels of RBM10 are associated with decreased sensitivity to an apoptogenic stimulus [ 4 ], and increased colony formation [ 2 ]. Mechanistically, RBM10 is involved in mRNA stabilization [ 5 ] and regulation of alternative splicing [ 2 , 3 , 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

Splicing arrays reveal novel RBM10 targets, including SMN2 pre-mRNA

et al. 2017

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BackgroundRBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. To accomplish this, we downregulated RBM10 in human cell lines, using small interfering RNAs, then monitored alternative splicing, using a reverse transcription-PCR screening platform.ResultsRBM10 knockdown (KD) provoked alterations in splicing events in 10–20% of the pre-mRNAs, most of which had not been previously identified as RBM10 targets. Hierarchical clustering of the genes affected by RBM10 KD revealed good conservation of alternative exon inclusion or exclusion across cell lines. Pathway annotation showed RAS signaling to be most affected by RBM10 KD. Of particular interest was the finding that splicing of SMN pre-mRNA, encoding the survival of motor neuron (SMN) protein, was influenced by RBM10 KD. Inhibition of RBM10 resulted in preferential expression of the full-length, exon 7 retaining, SMN transcript in four cancer cell lines and one normal skin fibroblast cell line. SMN protein is expressed from two genes, SMN1 and SMN2, but the SMN1 gene is homozygously disrupted in people with spinal muscular atrophy; as a consequence, all of the SMN that is expressed in people with this disease is from the SMN2 gene. Expression analyses using primary fibroblasts from control, carrier and spinal muscle atrophy donors demonstrated that RBM10 KD resulted in preferential expression of the full-length, exon 7 retaining, SMN2 transcript. At the protein level, upregulation of the full-length SMN2 was also observed. Re-expression of RBM10, in a stable RBM10 KD cancer cell line, correlated with a reversion of the KD effect, demonstrating specificity.ConclusionOur work has not only expanded the number of pre-mRNA targets for RBM10, but identified RBM10 as a novel regulator of SMN2 alternative inclusion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12867-017-0096-x) contains supplementary material, which is available to authorized users.

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Insight into the role of alternative splicing within the RBM10v1 exon 10 tandem donor site

Cited by 12 publications

References 29 publications

Functional role of RBM10 in lung adenocarcinoma proliferation

Functional role of RBM10 in lung adenocarcinoma proliferation

RBM10 promotes transformation-associated processes in small cell lung cancer and is directly regulated by RBM5

Splicing arrays reveal novel RBM10 targets, including SMN2 pre-mRNA

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