Identification of an Exon 4-Deletion Variant of Epidermal Growth Factor Receptor with Increased Metastasis-Promoting Capacity

Wang, Hai; Zhou, Min; Shi, Bizhi; Zhang, Qingli; Jiang, Hua; Sun, Yinghao; Liu, Jianhua; Zhou, Keke; Yao, Ming; Gu, Jianren; Yang, Shengli; Mao, Ying; Li, Zonghai

doi:10.1593/neo.101744

Cited by 62 publications

(53 citation statements)

References 31 publications

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“…Another example which designates alternative splicing in the formation of EGFR variants is in the case of the EGFR variant de4 EGFR. In this report, de4 EGFR was identified as an EGFR mutant with an aberrant splice joining of exons 3 and 5 and was expressed in 4/40 glioma tissues examined (Wang et al 2011). Similar to other EGFR mutants, de4 EGFR is intrinsically constitutively activated with a low basal tyrosine phosphorylation due to its ability to self-dimerize in the absence of ligand.…”

Section: Alternative Splicing Of Egfrmentioning

confidence: 80%

“…Similar to other EGFR mutants, de4 EGFR is intrinsically constitutively activated with a low basal tyrosine phosphorylation due to its ability to self-dimerize in the absence of ligand. Overexpression of de4 EGFR in U87 glioma cells resulted in increased proliferation, anchorage-independent colony formation, migration, and invasion (Wang et al 2011).…”

Section: Alternative Splicing Of Egfrmentioning

confidence: 95%

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Alternative RNA Splicing in the Pathogenesis of GBM

Thorne¹,

Cavenee²,

Furnari³

2015

MRAJ

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Abstract-Alternative splicing enables the generation of different proteins from a single gene, greatly increasing the use of genetic information. The resultant protein isoforms often have different biological properties effecting the phenotype of the cell in which it is expressed. Dysregulation of alternative splicing is a common occurrence in cancer and may lead to the formation of truncated or degraded proteins through the introduction of immature stop codons or nonsense mediated decay. Increasing evidence indicates that cancerassociated splicing variants play an important role in tumor initiation and progression. In this review, we summarize the evidence supporting the relevance of alternative splicing in glioblastoma multiforme (GBM). Specifically, we focus on the role of alternative splicing in GBM pathogenesis with an emphasis on the effect of aberrant alternative splicing of FGFR, GLI-1, and EGFR. The significance of exploiting alternatively spliced isoforms as potential biomarkers which may contribute to the development of diagnostic and prognostic methods, in addition to serving as molecular targets in GBM, will be discussed. Keywords-glioblastoma; alternative splicing Medical Research Archives 2015Issue 1 Copyright © 2015, Knowledge Enterprises Incorporated. All rights reserved. 2 INTRODUCTION Alternative splicing is a key regulator of gene expression and enables the generation of numerous transcripts from a single gene, thereby increasing the coding potential of the genome. During mRNA processing, approximately 90% of premRNA is removed as introns, with the remaining 10% joined together as exonic sequences (Tazi, Bakkour, and Stamm 2009). Thus the process has been considered a key driver in the evolution of phenotypic complexity. Splicing is the process by which introns are removed from a precursor mRNA (pre2mRNA) and exons are ligated to form a mature mRNA. Considered one of the most complicated RNA-protein complexes within the eukaryotic cell (Nilsen 2003), pre-mRNA splicing is catalyzed by the spliceosome, a large complex composed of five small nuclear ribonucleoprotein (RNP) subunits each composed of a single uridine rich small nuclear RNA (snRNA) in addition to as many as 150 proteins that assemble in an ordered stepwise manner on each intron to be spliced [reviewed in (Kim, Goren, and Ast 2008, Smith, Query, and Konarska 2008, Wahl, Will, and Luhrmann 2009. The spliceosome performs the two primary functions of splicing: recognition of the intron/exon boundaries and catalysis of the cut and paste reactions that remove introns and join exons. It is responsible for directing both constitutive and alternative splicing (Faustino and Cooper 2003).Definition of the exon/intron boundary is maintained through cis-regulatory RNA elements which serve as splicing enhancers or silencers, essentially determining the splice site. Splicing regulatory elements (SREs) fall into four different categories: exonic splicing enhancers (ESEs), intronic splicing enhancers (ISEs), exonic splicing silencers (ESSs), and in...

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Section: Alternative Splicing Of Egfrmentioning

confidence: 80%

Section: Alternative Splicing Of Egfrmentioning

confidence: 95%

Alternative RNA Splicing in the Pathogenesis of GBM

Thorne¹,

Cavenee²,

Furnari³

2015

MRAJ

View full text Add to dashboard Cite

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“…Moreover, most of them are soluble receptors, lacking an intracellular domain and difficult to mediate ligand-induced signal transductions. Some mutant splicing variants of EGFR have also been reported previously (20,21). A well-recognized one is EGFRvIII.…”

Section: Introductionmentioning

confidence: 82%

A Novel EGFR Isoform Confers Increased Invasiveness to Cancer Cells

et al. 2013

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As a validated therapeutic target in several human cancers, the EGF receptor (EGFR) provides a focus to gain deeper insights into cancer pathophysiology. In this study, we report the identification of a naturally occurring and widely expressed EGFR isoform termed EGFRvA, which substitutes a Ser/Thr-rich peptide for part of the carboxyl-terminal regulatory domain of the receptor. Intriguingly, EGFRvA expression relates more closely to histopathologic grade and poor prognosis in patients with glioma. Ectopic expression of EGFRvA in cancer cells conferred a higher invasive capacity than EGFR in vitro and in vivo. Mechanistically, EGFRvA stimulated expression of STAT3, which upregulated heparin-binding EGF (HB-EGF). Reciprocally, HB-EGF stimulated phosphorylation of EGFRvA at Y845 along with STAT3, generating a positive feedback loop that may reinforce invasive function. The significance of EGFRvA expression was reinforced by findings that it is attenuated by miR-542-5p, a microRNA that is a known tumor suppressor. Taken together, our findings define this newfound EGFR isoform as a key theranostic molecule. Cancer Res; 73(23); 7056-67. Ó2013 AACR.

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“…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. We hypothesized that if exposure to environmental chemicals altered organoid development, the mechanisms might include their effects on the expression of particular protein isoforms (60). To investigate changes in splicing across the proteome, we took advantage of the copious sequence data produced by the MS/MSbased proteomic approach used in this study.…”

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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Identification of an Exon 4-Deletion Variant of Epidermal Growth Factor Receptor with Increased Metastasis-Promoting Capacity

Cited by 62 publications

References 31 publications

Alternative RNA Splicing in the Pathogenesis of GBM

Alternative RNA Splicing in the Pathogenesis of GBM

A Novel EGFR Isoform Confers Increased Invasiveness to Cancer Cells

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

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