Co- and post-transcriptional regulation of Rbm5 and Rbm10 in mouse cells as evidenced by tissue-specific, developmental and disease-associated variation of splice variant and protein expression levels

Ozuemba, Bartholomew; Masilamani, Twinkle; Loiselle, Julie J.; Koenderink, Benjamin W; Vanderbeck, Kaitlin; Knee, Jose M.; Larivière, Céline; Sutherland, Leslie C.

doi:10.1016/j.gene.2015.12.070

Cited by 5 publications

(3 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although Rodor et al . strongly associated RBM10 with the regulation of alternative splicing in that study [75], as mouse cells in general express RBM5 [76], this could be an RBM5-dependant function of RBM10, as we propose above.…”

Section: Discussionmentioning

confidence: 55%

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

2017

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 55%

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

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since RBM10 is ubiquitously expressed, its role in the regulation of housekeeping or ubiquitously expressed transcripts is probably conserved in different cell types or during development. 33 However, RBM10 might also play a role in the regulation of transcripts with specific expression profile. To assess how RBM10 affects splicing in a different mouse cell line, we took advantage of the availability of an RBM10 KO ES cell line.…”

Section: Resultsmentioning

confidence: 99%

The RNA-binding landscape of RBM10 and its role in alternative splicing regulation in models of mouse early development

et al. 2016

View full text Add to dashboard Cite

Mutations in the RNA-binding protein, RBM10, result in a human syndromic form of cleft palate, termed TARP syndrome. A role for RBM10 in alternative splicing regulation has been previously demonstrated in human cell lines. To uncover the cellular functions of RBM10 in a cell line that is relevant to the phenotype observed in TARP syndrome, we used iCLIP to identify its endogenous RNA targets in a mouse embryonic mandibular cell line. We observed that RBM10 binds to pre-mRNAs with significant enrichment in intronic regions, in agreement with a role for this protein in pre-mRNA splicing. In addition to protein-coding transcripts, RBM10 also binds to a variety of cellular RNAs, including non-coding RNAs, such as spliceosomal small nuclear RNAs, U2 and U12. RNA-seq was used to investigate changes in gene expression and alternative splicing in RBM10 KO mouse mandibular cells and also in mouse ES cells. We uncovered a role for RBM10 in the regulation of alternative splicing of common transcripts in both cell lines but also identified cell-type specific events. Importantly, those pre-mRNAs that display changes in alternative splicing also contain RBM10 iCLIP tags, suggesting a direct role of RBM10 in these events. Finally, we show that depletion of RBM10 in mouse ES cells leads to proliferation defects and to gross alterations in their differentiation potential. These results demonstrate a role for RBM10 in the regulation of alternative splicing in two cell models of mouse early development and suggests that mutations in RBM10 could lead to splicing changes that affect normal palate development and cause human disease.

show abstract

“…In addition, the expression of RBM10 in NCTs was also consistent with the low expression of our cytological experiments in HLFs. As RBM10 can affect the metabolism of DNA molecules and a variety of cellular processes, it is necessary for the development (34,35), growth and metabolism of normal cells (14,36).…”

Section: Discussionmentioning

confidence: 99%

Functional role of RBM10 in lung adenocarcinoma proliferation

et al. 2018

View full text Add to dashboard Cite

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.

show abstract

Co- and post-transcriptional regulation of Rbm5 and Rbm10 in mouse cells as evidenced by tissue-specific, developmental and disease-associated variation of splice variant and protein expression levels

Cited by 5 publications

References 53 publications

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

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

The RNA-binding landscape of RBM10 and its role in alternative splicing regulation in models of mouse early development

Functional role of RBM10 in lung adenocarcinoma proliferation

Contact Info

Product

Resources

About