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Schell, Thomas; Kulozik, Andreas E.; Hentze, Matthias W.

doi:10.1186/gb-2002-3-3-reviews1006

Cited by 77 publications

(16 citation statements)

References 36 publications

(57 reference statements)

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“…Western blot analysis on the protein extracts obtained from AML blasts of two mutants (#2236 and 3102) failed to show the expression of truncated ETV6 proteins. Generally, the absence of abnormal protein is justified by the possible degradation of mutant transcripts through a nonsense-mediated mRNA decay pathway (Losson and Lacroute, 1979;Frischmeyer and Dietz, 1999;Schell et al, 2002). Nucleotide sequence analysis on patient #2236 demonstrated that the mutant transcript level was decreased to only one-third of the wt level (data not shown).…”

Section: Discussionmentioning

confidence: 97%

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

et al. 2005

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ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization-or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.

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Section: Discussionmentioning

confidence: 97%

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

et al. 2005

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“…Our experimental data further indicate that human U2AF 35 c mRNAs are targeted to NMD, a mechanism by which cells selectively recognize and degrade mRNAs that contain premature termination codons (for recent reviews see Refs. [52][53][54] surveillance mechanism that destroys aberrant mRNAs generated as a result of biosynthetic errors or gene mutations, it was recently proposed that NMD additionally participates in a pathway that controls expression of a large number of genes (5). Based on a bioinformatic approach, Lewis et al (5) predicted that 35% of human EST-suggested alternative isoforms contain premature termination codons and are potential targets for NMD.…”

Section: Discussionmentioning

confidence: 99%

Diversity of Vertebrate Splicing Factor U2AF35

Pacheco

Gomes

Barbosa‐Morais

et al. 2004

Journal of Biological Chemistry

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35 b varies from 10-fold in the brain to 20-fold in skeletal muscle. We propose that post-transcriptional regulation of U2AF1 gene expression may provide a mechanism by which the relative cellular concentration and availability of U2AF 35 protein isoforms are modulated, thus contributing to the finely tuned control of splicing events in different tissues.In higher eukaryotes, most protein-coding genes contain sequences that are spliced from the nascent transcripts (pre-mRNAs) in the nucleus. Intron excision is carried out by an assembly of small nuclear RNAs and proteins that are collectively recruited to pre-mRNAs forming the spliceosome (reviewed in Ref. 1). Although introns are excised with a high degree of precision, for many pre-mRNAs there is flexibility in the choice of alternative splice sites, often in response to tissuespecific, physiologically or developmentally regulated states. Alternative splicing produces multiple mRNAs encoding distinct proteins, thus expanding the coding capacity of genes and contributing to the proteomic complexity of higher organisms (2-4). Moreover, alternative splicing may contribute to regulate protein expression by generating premature termination codons that target the transcript to nonsense-mediated mRNA decay (5).In metazoans, pre-mRNA sequences implicated in splicing are only weakly conserved. Multiple, relatively weak proteinprotein and protein-RNA interactions involving these sequences and additional regulatory sequence elements, which can positively or negatively affect spliceosome assembly at nearby splice sites, constitute the basis to control alternative splicing (for recent reviews see Refs. 4, 6, and 7). Proteins that bind to pre-mRNA and affect splicing regulation include SR proteins, hnRNPs, 1 and tissue-or developmental stage-specific factors. Individual SR proteins interact only weakly with enhancer elements, but their binding to pre-mRNA is highly cooperative and can lead to recognition of distinct RNA sequence motifs, thus contributing to the selection of regulated splice sites. A distinct role is played by hnRNP proteins, which in general antagonize the stimulatory activity of SR proteins, and cell type-specific proteins, which may either inhibit or promote splicing. Thus, control of alternative splicing is achieved through the combinatorial interplay of both regulatory sequence signals and trans-acting protein factors (4,8,9).The spliceosome is a multicomponent RNA-protein machine containing five uracil-rich small nuclear ribonucleoproteins (U snRNPs) and many non-snRNP protein splicing factors. In the late 1990s ϳ100 splicing factors were identified (10), and since then the number has nearly doubled (1). Initiation of spliceosome recruitment to a pre-mRNA involves recognition of the 5Ј splice site by the U1 snRNP, whereas the U2 snRNP associates with the 3Ј region of the intron. The establishment of a stable interaction between U2 snRNP and pre-mRNA requires an auxiliary factor, U2AF (11). The U2

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“…Furthermore, the EJC contains several proteins involved in NMD, including the well-characterized NMD proteins UPF2 and UPF3b (80). Together with several other lines of evidence (7,(81)(82)(83), a strong case can be made for the idea that the EJC relays the previous location of introns relative to the stop codon to ultimately dictate whether or not rapid mRNA decay will be elicited.…”

Section: Nmd and The Exon-junction Complexmentioning

confidence: 99%

The Nonsense-Mediated Decay RNA Surveillance Pathway

Chang

Imam

Wilkinson

2007

Annu. Rev. Biochem.

1,110

973

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Nonsense-mediated mRNA decay (NMD) is a quality-control mechanism that selectively degrades mRNAs harboring premature termination (nonsense) codons. If translated, these mRNAs can produce truncated proteins with dominant-negative or deleterious gain-of-function activities. In this review, we describe the molecular mechanism of NMD. We first cover conserved factors known to be involved in NMD in all eukaryotes. We then describe a unique protein complex that is deposited on mammalian mRNAs during splicing, which defines a stop codon as premature. Interaction between this exon-junction complex (EJC) and NMD factors assembled at the upstream stop codon triggers a series of steps that ultimately lead to mRNA decay. We discuss whether these proofreading events preferentially occur during a "pioneer" round of translation in higher and lower eukaryotes, their cellular location, and whether they can use alternative EJC factors or act independent of the EJC.

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Untitled

Cited by 77 publications

References 36 publications

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

Diversity of Vertebrate Splicing Factor U2AF35

The Nonsense-Mediated Decay RNA Surveillance Pathway

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