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Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation (CLIP-Seq)

ABSTRACT: RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. CLIP-Seq analysis of RBM5, RBM6 and RBM10, with 2 biological replicates and one non-specific control for each protein.

ORGANISM(S): Homo sapiens

SUBMITTER: Bechara EG

PROVIDER: S-ECPF-GEOD-48066 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation (CLIP-Seq)

Project description:RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. CLIP-Seq analysis of RBM5, RBM6 and RBM10, with 2 biological replicates and one non-specific control for each protein.

2013-12-20 | E-GEOD-48066 | biostudies-arrayexpress

Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation

Project description:RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. RNA from 3 biological replicates of knockdowns of RBM5, 6 and 10 and a control set were used. Changes between the control and knockdowns were measured based on using a splice-junction array (Affymetrix HJAY).

| S-ECPF-GEOD-47431 | biostudies-other

Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation (CLIP-Seq)

2013-12-20 | GSE48066 | GEO

Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation

Project description:RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. RNA from 3 biological replicates of knockdowns of RBM5, 6 and 10 and a control set were used. Changes between the control and knockdowns were measured based on using a splice-junction array (Affymetrix HJAY).

2013-12-20 | E-GEOD-47431 | biostudies-arrayexpress

Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation

2013-12-20 | GSE47431 | GEO

Alternative splicing regulation of cell-cycle genes by SPF45/SR140/CHERP complex controls cell proliferation.

Project description:The regulation of pre-mRNA processing has important consequences for cell division and the control of cancer cell proliferation, but the underlying molecular mechanisms remain poorly understood. We report that three splicing factors, SPF45, SR140, and CHERP, form a tight physical and functionally coherent complex that regulates a variety of alternative splicing events, frequently by repressing short exons flanked by suboptimal 3' splice sites. These comprise alternative exons embedded in genes with important functions in cell-cycle progression, including the G2/M key regulator FOXM1 and the spindle regulator SPDL1. Knockdown of either of the three factors leads to G2/M arrest and to enhanced apoptosis in HeLa cells. Promoting the changes in FOXM1 or SPDL1 splicing induced by SPF45/SR140/CHERP knockdown partially recapitulates the effects on cell growth, arguing that the complex orchestrates a program of alternative splicing necessary for efficient cell proliferation.

| S-EPMC8594467 | biostudies-literature

Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma.

Project description:UnlabelledThe cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline-rich region (PRR(L) ) compared to the other with a short PRR (PRR(S) ). Recently, PRR(L) was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRR(L) expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRR(L) generally promotes and PRR(S) suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRR(S) leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRR(S) knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA-binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein-specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRR(L) , while SRPK2 knockdown causes accumulation of PRR(S) . The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRR(S) . Finally, HCC cell lines that predominantly express PRR(L) are differentially sensitive to heat shock protein 90 inhibition.ConclusionAlternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable.

| S-EPMC4589429 | biostudies-literature

Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk.

Project description:NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration.

| S-EPMC9027642 | biostudies-literature

Alternative splicing regulation of cell cycle genes by SPF45/SR140/CHERP complex controls cancer cell proliferation

Project description:SPF45, SR140 and CHERP were knock downed using lentiviral delivery of shRNAs in HeLa cells

2021-07-30 | GSE180892 | GEO

PPIB-regulated alternative splicing of cell cycle genes contributes to the regulation of cell proliferation.

Project description:BackgroundPeptidylprolyl cis-trans isomerase B (PPIB) plays an important role in the process of inflammation through binding RNA, but the molecular pathogenesis is not yet clearly understood. The objective of this study was to investigate and verify the PPIB-regulated gene expressions and alternative splicing in Hela cells.MethodsWe examined the PPIB-regulated transcriptomes in HeLa cells using RNA-seq data. Differentially expressed genes, alternative splicing analysis were carried out. Functional enrichment analysis was used to define the enrichment of each term.ResultsWe found that PPIB knockdown successfully downregulated PPIB in Hela cells, which promoted cell proliferation (P < 0.001), but no significant effect on cell apoptosis. Ten alternative splicing genes regulated by PPIB were detected in Hela cells. The ten top Gene Ontology biological process analysis and functional pathways of the alternative splicing genes were screened and identified. The pathways where differentially expressed genes are most enriched were toll-like receptor 4 signaling pathways and other signaling pathways relating to inflammation and immune response. In addition, PPIB affects the alternative splicing of multiple genes, and the Gene Ontology-biological process analysis showed that genes significantly related to alternative splicing changes were mainly enriched in the cell cycle (P < 0.05).ConclusionPPIB regulates the alternative splicing of cell cycle-related genes to affect cell proliferation and regulate the occurrence and development of chronic inflammatory diseases such as Nasal polyps.

| S-EPMC9556483 | biostudies-literature

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