Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins.

Mayeda, Akila; Munroe, Stephen H.; Cáceres, Javier F.; Krainer, Adrian R.

doi:10.1002/j.1460-2075.1994.tb06883.x

Cited by 312 publications

(334 citation statements)

References 88 publications

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“…This interaction is mediated by a C-terminal nuclear localization sequence of hnRNP A2, called the M9 domain (Izaurralde et al, 1997). HnRNP A2 also contains a glycine-rich domain that has been implicated in protein-protein interactions (Mayeda et al, 1994). Our yeast two-hybrid screen indicates that the C-terminal portion of TOG is sufficient for binding to hnRNP A2.…”

Section: Discussionmentioning

confidence: 89%

The Microtubule-associated Protein Tumor Overexpressed Gene Binds to the RNA Trafficking Protein Heterogeneous Nuclear Ribonucleoprotein A2

Kosturko

Maggipinto

D'Sa

et al. 2005

MBoC

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In neural cells, such as oligodendrocytes and neurons, transport of certain RNAs along microtubules is mediated by the cis-acting heterogeneous nuclear ribonucleoprotein A2 response element (A2RE) trafficking element and the cognate trans-acting heterogeneous nuclear ribonucleoprotein (hnRNP) A2 trafficking factor. Using a yeast two-hybrid screen, we have identified a microtubule-associated protein, tumor overexpressed gene (TOG)2, as an hnRNP A2 binding partner. The C-terminal third of TOG2 is sufficient for hnRNP A2 binding. TOG2, the large protein isoform of TOG, is the only isoform detected in oligodendrocytes in culture. TOG coimmunoprecipitates with hnRNP A2 present in the cytoskeleton (CSK) fraction of neural cells, and both coprecipitate with microtubule stabilized pellets. Staining with anti-TOG reveals puncta that are localized in proximity to microtubules, often at the plus ends. TOG is colocalized with hnRNP A2 and A2RE-mRNA in trafficking granules that remain associated with CSK-insoluble tissue. These data suggest that TOG mediates the association of hnRNP A2-positive granules with microtubules during transport and/or localization. INTRODUCTIONThe heterogeneous nuclear ribonucleoprotein (hnRNP) A2 is implicated in RNA processing, RNA transport, and translation regulation (Dreyfuss et al., 1993;Siomi and Dreyfuss, 1995;Hamilton et al., 1999;Kwon et al., 1999). HnRNP A2 binds to a specific cis-acting element, hnRNP A2 response element (A2RE), found in several dendritically localized mRNAs Munro et al., 1999). This interaction is necessary for transport of A2RE-mRNAs to the periphery of neural cells (Munro et al., 1999;Shan et al., 2003).A2RE-mRNAs, hnRNP A2, and other components form complexes that look by light microscopy like granules that are transported to the cell periphery by a microtubule-and kinesin-based mechanism. In cultured oligodendrocytes and neurons, granules containing A2RE-mRNAs and hnRNP A2 are associated with the cytoskeleton (CSK) . HnRNP A2 and some A2RE-mRNAs copurify with the CSK from rat brain (Hoek et al., 1998;Boccaccio et al., 1999).To identify molecular partners of hnRNP A2, we performed yeast two-hybrid analysis. One of the components identified is the tumor overexpressed gene (TOG) protein, a microtubule-associated protein (MAP) ubiquitously expressed in human tissues. TOG is a single copy gene that generates two mRNA splice variants (Nagase et al., 1995;Charrasse et al., 1998) encoding proteins that differ by a 60-aa insert near the C terminus. In dividing cells, TOG localizes with centrosome and spindle microtubules and may be necessary for microtubule rearrangements and spindle assembly (Charrasse et al., 1998;Lee et al., 2001). Orthologues of colonic and hepatic tumor overexpressed gene (ch-TOG) (Homo sapiens), Dis1p, Stu2p, XMAP215, ZYG-9, and mini spindles, in fission yeast, budding yeast, Xenopus laevis, Caenorhabditis elegans, and Drosophila melanogaster, respectively, have similar functions. TOG and its orthologues all contain multiple HEAT repeats that may serv...

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Section: Discussionmentioning

confidence: 89%

The Microtubule-associated Protein Tumor Overexpressed Gene Binds to the RNA Trafficking Protein Heterogeneous Nuclear Ribonucleoprotein A2

Kosturko

Maggipinto

D'Sa

et al. 2005

MBoC

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“…Like all canonical RRMs, the RBFOX1 RRM utilizes the b-sheet to bind nucleic acids; two exposed phenylalanine residues in the RNP (ribonucleoprotein) submotifs are essential for binding to RNA by intercalating with single-stranded bases (Auweter et al 2006). We mutated the two phenylalanines to aspartic acids, which was reported to eliminate RNA binding (Mayeda et al 1994;Auweter et al 2006), and tested whether the resulting protein can still enhance exon skipping when tethered via MS2. To our surprise, the 2 amino acid substitution completely abolished the exon repression activity, even though the protein is still tethered to the minigene transcript through MS2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

Sun¹,

Zuo²,

Fregoso³

et al. 2011

RNA

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RBFOX1 and RBFOX2 are alternative splicing factors that are predominantly expressed in the brain and skeletal muscle. They specifically bind the RNA element UGCAUG, and regulate alternative splicing positively or negatively in a position-dependent manner. The molecular basis for the position dependence of these and other splicing factors on alternative splicing of their targets is not known. We explored the mechanisms of RBFOX splicing activation and repression using an MS2-tethering assay. We found that the Ala/Tyr/Gly-rich C-terminal domain is sufficient for exon activation when tethered to the downstream intron, whereas both the C-terminal domain and the central RRM are required for exon repression when tethered to the upstream intron. Using immunoprecipitation and mass spectrometry, we identified hnRNP H1, RALY, and TFG as proteins that specifically interact with the C-terminal domain of RBFOX1 and RBFOX2. RNA interference experiments showed that hnRNP H1 and TFG modulate the splicing activity of RBFOX1/2, whereas RALY had no effect. However, TFG is localized in the cytoplasm, and likely modulates alternative splicing indirectly.

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“…These include hnRNP A1 18 and other hnRNP A/B family members (hnRNP A1B, A2 and B1). 19 These proteins are associated with most, if not all, nascent mRNA transcripts in vivo and play an important role in RNA transport. hnRNP A1 also contributes to the regulation of alternative splicing with increasing concentrations favoring the use of distal 5 0 splice sites, while limiting hnRNP A1 expression encourages the use of proximal 5 0 splice sites.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms regulating the tumor-targeting potential of splice-activated gene expression

Hayes

Dougherty

Davis³

et al. 2004

Cancer Gene Ther

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Previous studies have suggested that differences in the ability of normal and malignant cells to process certain alternatively spliced pre-mRNA transcripts can be exploited as a potentially powerful means of targeting the expression of therapeutic genes to tumor cells in vivo and in vitro. Specifically, it was shown that efficient processing of minigene constructs containing the alternatively spliced CD44 exons v9 and v10 only occurs in tumor cells that express CD44 isoforms that incorporate these exons (e.g. CD44R1). In the present study, efforts were made to define the molecular mechanisms that underlie the apparent specificity of this process. RT-PCR analysis and DNA sequencing were used to characterize the various splicing events that occur between CD44 exons v8, v9 and v10 following transfection of minigene constructs containing these various exons into CD44R1-positive (PC3) and CD44R1-negative (T24) cell lines. The results obtained confirm that although the v8-v9 intron is efficiently removed in both CD44R1-positive and CD44R1-negative cells, the corresponding v9-v10 intron is accurately spliced and the exons appropriately joined only in lines that express v10-containing CD44 isoforms (e.g. PC3). In CD44R1-negative cell lines (e.g. T24) alternative 5 0 and 3 0 splice sites located within the v9-v10 intron are preferentially used, resulting in various portions of the intron being retained within the final processed mRNA product. It is proposed that identification of these functionally important intronic sequence elements will facilitate the development of second generation ''splice activated gene expression'' vectors that may prove useful in various cancer gene therapy applications.

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Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins.

Cited by 312 publications

References 88 publications

The Microtubule-associated Protein Tumor Overexpressed Gene Binds to the RNA Trafficking Protein Heterogeneous Nuclear Ribonucleoprotein A2

The Microtubule-associated Protein Tumor Overexpressed Gene Binds to the RNA Trafficking Protein Heterogeneous Nuclear Ribonucleoprotein A2

Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

Molecular mechanisms regulating the tumor-targeting potential of splice-activated gene expression

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