Hallmarks of alternative splicing in cancer

Oltean, Sebastian; Bates, David O.

doi:10.1038/onc.2013.533

Cited by 591 publications

(562 citation statements)

References 94 publications

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“…It is conceivable that one of the many SNPs present in the introns between exon 21 and 22, or exon 22 and 23 may contribute to splicing ratios of ΔS/S and α/β respectively. The assay could be used to quantify STAT3 transcripts in cancerous cells, where mutations or changes in splicing regulation may introduce bias to the splicing process 40 . Mutations in splicing factors (like SF3B1), as observed in myelodysplastic syndromes 41 may also lead to changes that can be measured by this protocol.…”

Section: Discussionmentioning

confidence: 99%

Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts

Turton

Esnault

Delain

et al. 2016

JoVE

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Human signal transducer and activator of transcription 3 (STAT3) is one of many genes containing a tandem splicing site. Alternative donor splice sites 3 nucleotides apart result in either the inclusion (S) or exclusion (ΔS) of a single residue, Serine-701. Further downstream, splicing at a pair of alternative acceptor splice sites result in transcripts encoding either the 55 terminal residues of the transactivation domain (α) or a truncated transactivation domain with 7 unique residues (β). As outlined in this manuscript, measuring the proportions of STAT3's four spliced transcripts (Sα, Sβ, ΔSα and ΔSβ) was possible using absolute qPCR (quantitative polymerase chain reaction). The protocol therefore distinguishes and measures highly similar splice variants. Absolute qPCR makes use of calibrator plasmids and thus specificity of detection is not compromised for the sake of efficiency. The protocol necessitates primer validation and optimization of cycling parameters. A combination of absolute qPCR and efficiency-dependent relative qPCR of total STAT3 transcripts allowed a description of the fluctuations of STAT3 splice variants' levels in eosinophils treated with cytokines. The protocol also provided evidence of a co-splicing interdependence between the two STAT3 splicing events. The strategy based on a combination of the two qPCR techniques should be readily adaptable to investigation of cosplicing at other tandem splicing sites.

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Section: Discussionmentioning

confidence: 99%

Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts

Turton

Esnault

Delain

et al. 2016

JoVE

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“…In addition to changes in protein abundance, alterations in isoform expression constitute proteome alterations that are dynamically regulated during development and tumorigenesis (59). For example, alternative splicing of epidermal growth factor receptor results in the expression of a constitutively active isoform that is selectively expressed in prostate and ovarian cancers but not in the normal tissues from which they arise.…”

Section: Functional Classes Of Proteins and Pathways Changed By Exposmentioning

confidence: 99%

Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals

Williams

Lemieux

Hassis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Common environmental contaminants such as bisphenols and phthalates and persistent contaminants such as polychlorinated biphenyls are thought to influence tissue homeostasis and carcinogenesis by acting as disrupters of endocrine function. In this study we investigated the direct effects of exposure to bisphenol A (BPA), mono-n-butyl phthalate (Pht), and polychlorinated biphenyl 153 (PCB153) on the proteome of primary organotypic cultures of the mouse mammary gland. At low-nanomolar doses each of these agents induced distinct effects on the proteomes of these cultures. Although BPA treatment produced effects that were similar to those induced by estradiol, there were some notable differences, including a reduction in the abundance of retinoblastomaassociated protein and increases in the Rho GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle protein CDC42. Both Pht and PCB153 induced changes that were distinct from those induced by estrogen, including decreased levels of the transcriptional corepressor C-terminal binding protein 1. Interestingly, the three chemicals appeared to alter the abundance of distinct splice forms of many proteins as well as the abundance of several proteins that regulate RNA splicing. Our combined results indicate that the three classes of chemical have distinct effects on the proteome of normal mouse mammary cultures, some estrogen-like but most estrogen independent, that influence diverse biological processes including apoptosis, cell adhesion, and proliferation.proteomics | mammary epithelium | environmental chemicals | organotypic culture | estrogen B reast cancers are caricatures of normal tissue development (1-3). The same underlying mechanisms that affect the cell processes needed for normal mammary development contribute to cancer progression. By affecting the distribution of interacting cells and communication among them through nontargeted effects, carcinogens can promote the outgrowth of altered cells with malignant potential. Exposure to environmental agents can affect mammary gland development and alter breast cancer risk. Epidemiologic studies have associated a number of environmental factors with increased breast cancer risk (4). Some of these factors may have low-level effects that are not genotoxic but alter immune responses, vascularity, or the microenvironment or that change susceptibility to carcinogens. A current weakness in models of cancer risk assessment is the lack of consideration of factors that influence the susceptibility of mixed cell populations to transformation. Indeed, ionizing radiation, the prototypical carcinogen, promotes changes in the biochemical properties in cultured mouse and human breast cells, in the stromal environment, and in intact mouse mammary gland (5-7).Physiologically relevant 3D culture models can recapitulate crucial aspects of the dynamic and reciprocal signaling necessary for establishing and maintaining tissue-specific morphogenetic programs. The determination of the molecular mechanisms underlying m...

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“…Aberrant pre-mRNA splicing is a hallmark of cancer and contributes to numerous aspects of tumour biology 24,25 . Cancer associated changes in AS have been linked to altered expression of numerous RNA binding proteins, some of which are oncogenic or act as tumour suppressors, as well as to splicing-sensitive disease mutations that impact the levels or activities of other cancer-associated genes 26 .…”

Section: Whippet Detects Global Increases In High-entropy As In Cancementioning

confidence: 99%

Whippet: an efficient method for the detection and quantification of alternative splicing reveals extensive transcriptomic complexity

Sterne-Weiler

Weatheritt

Best

et al. 2017

Preprint

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Alternative splicing (AS) is a widespread process underlying the generation of transcriptomic and proteomic diversity in metazoans. Major challenges in comprehensively detecting and quantifying patterns of AS are that RNA-seq datasets are expanding near exponentially, while existing analysis tools are computationally inefficient and ineffective at handling complex splicing patterns. Here, we describe Whippet, a method that rapidly, and with minimal hardware requirements, models and quantifies splicing events of any complexity without significant loss of accuracy.Using an entropic measure of splicing complexity, Whippet reveals that approximately 33% of human protein coding genes contain complex AS events that result in substantial expression of multiple splice isoforms. These events frequently affect tandem arrays of folded protein domains. Remarkably, high-entropy AS events are more prevalent in tumour relative to matched normal tissues, and these differences correlate with increased expression of proto-oncogenic splicing factors. Whippet thus affords the rapid and accurate analysis of AS events of any complexity, and as such will facilitate biomedical research.

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Hallmarks of alternative splicing in cancer

Cited by 591 publications

References 94 publications

Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts

Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts

Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals

Whippet: an efficient method for the detection and quantification of alternative splicing reveals extensive transcriptomic complexity

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