Paraneoplastic Encephalomyelitis Antigens Bind to the AU-rich Elements of mRNA

Liu, J.; Dalmau, Josep; Szabó, Angela E.; Rosenfeld, Myrna R.; Huber, Julia; Furneaux, Henry

doi:10.1212/wnl.45.3.544

Cited by 120 publications

(97 citation statements)

References 14 publications

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“…It encodes the most common isoform, HuD, lacking the second alternate exon in the hinge domain (amino acid residues 252 to 265) (30) and carries C-terminal hexahistidine and MYC epitope tags. The HuB expression plasmid (pET3d-Hel-N1, F622) contains the same epitope tags as F578 and was derived by PCR from plasmid pCMVHel-N1 (kindly provided by Drs.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA

Park-Lee

Kim

Laird-Offringa

2003

Journal of Biological Chemistry

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Hu proteins have been shown to bind to AU-rich elements (AREs) in the 3 -untranslated region of unstable mRNAs. They can thereby inhibit the decay of labile transcripts by antagonizing destabilizing proteins that target these AU-rich sequences. Here we examine the sequence preferences of HuD to elucidate its possible role in counteracting mRNA decay. Using repeats of the prototype destabilizing sequence UU(AUUU) n AUU, we show that all three HuD RNA-binding domains participate in binding to AU-tracts that can be as short as 13 residues, depending on the position of the remaining As. Removal of the A residues, resulting in a poly(U)-tract, increased the affinity of HuD for RNA, suggesting that the presence of As in destabilizing elements might favor the recruitment of other proteins and/or prevent HuD from binding too tightly to AREs. In vitro selection experiments with randomized RNAs confirmed the preference of HuD for poly(U). RNA binding analysis of the related protein HuB showed a similar preference for poly(U). In contrast, tristetraprolin, an mRNA destabilizing protein, strongly prefers AU-rich RNA. Many labile mRNAs contain U-tracts in or near their AREs. Individual AREs may thus differentially affect mRNA halflife by recruiting a unique complement of stabilizing and destabilizing factors.

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Section: Methodsmentioning

confidence: 99%

Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA

Park-Lee

Kim

Laird-Offringa

2003

Journal of Biological Chemistry

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“…Members of the embryonic lethal abnormal vision (ELAV) family of proteins have been shown to bind with high affinity to AREs within the 3Ј-UTR of mRNAs of genes involved in cellular growth and neuronal differentiation (20,(33)(34)(35)(36)(37). The functional significance of the interactions between AREs and ELAV proteins has been investigated, and a number of studies have demonstrated that ELAV proteins inhibit ARE-mediated mRNA turnover (28, 31, 33, 38 -41).…”

Section: Neuroblastoma (Nb)mentioning

confidence: 99%

“…At least 14 apparently distinct AREbinding proteins have been identified in eukaryotic cell extracts by UV-cross-linking and gel shift assays (reviewed in Ref. 26), and there is evidence indicating that binding of these trans-acting factors to AREs influences mRNA degradation (27)(28)(29)(30)(31)(32).Members of the embryonic lethal abnormal vision (ELAV) family of proteins have been shown to bind with high affinity to AREs within the 3Ј-UTR of mRNAs of genes involved in cellular growth and neuronal differentiation (20,(33)(34)(35)(36)(37). The functional significance of the interactions between AREs and ELAV proteins has been investigated, and a number of studies have demonstrated that ELAV proteins inhibit ARE-mediated mRNA turnover (28, 31, 33, 38 -41).…”

mentioning

confidence: 99%

HuD, a Neuronal-specific RNA-binding Protein, Increases thein Vivo Stability of MYCN RNA

Manohar¹,

Short²,

Nguyen³

et al. 2002

Journal of Biological Chemistry

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MYCN amplification and consequent deregulated expression plays a crucial role in determining the clinical behavior of neuroblastoma. Enhanced expression of MYCN confers growth potential to neuroblastoma cells, and a direct link between MYCN expression and the development of neuroblastoma has been demonstrated in transgenic mice studies. Although the molecular pathways underlying the regulation of MYCN have not been fully elucidated, post-transcriptional mechanisms appear to be important. Previously, we reported that an embryonic lethal abnormal vision-like (ELAV) protein binds with high specificity to at least two AU-rich elements within the MYCN 3-untranslated region. In this study, we characterized the ability of cis-acting elements within the MYCN 3-untranslated region to destabilize mRNA in cells and examined the functional consequences of its interactions with the ELAV protein HuD. We show that at least 4 cis-acting elements within the MYCN 3-untranslated region are able to signal the degradation of stable heterologous mRNA. Ectopic overexpression of HuD dramatically inhibits RNA decay mediated by the full-length MYCN 3-untranslated region and cis-acting destabilizing elements that harbor HuD binding sites in vivo. HuD may contribute to the malignant phenotype of neuroblastoma cells by stabilizing MYCN mRNA, thereby enhancing steady-state levels of expression of this oncogene. Neuroblastoma (NB),1 a neoplasm that arises from embryonic neural crest tissue, is the second-most common solid pediatric tumor (1). MYCN is amplified in ϳ25% of primary NBs (2-4), and MYCN overexpression is frequently detected in NB tumors (5). Although the clinical significance of MYCN expression in NB tumors that lack MYCN amplification remains controversial (6 -10), a strong correlation between high levels of MYCN expression consequent to genomic amplification of this oncogene and aggressive disease is well established (3-5, 11). Laboratory experiments have further supported an important role for MYCN in determining NB phenotype. Ectopic overexpression of MYCN results in enhanced malignant growth (12, 13), whereas MYCN antisense studies performed by our laboratory and others have shown that down-regulation of MYCN in human NB is associated with a decrease in cellular proliferation and inhibited tumor cell growth in vitro (14 -16). Furthermore, a direct link between MYCN expression and the development of NB has been demonstrated in transgenic mice studies (17).Previously we examined MYCN regulation in N-(neuroblastic, tumorigenic) and S-type (substrate-adherent, non-tumorigenic) subclones (W-N and W-S) of the MYCN-amplified NB cell line NBL-W (18). In addition to distinct morphology and growth characteristics, the subclones have differential levels of MYCN expression despite having the same genomic MYCN copy number. We found that the disparity in steady-state levels of MYCN mRNA in the W-N and W-S cells was largely determined by differences in MYCN mRNA stability (19). Lazarova and co-workers (20) examined MYCN expression in other ...

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“…To characterize the m-Msi-1-expressing cells in this region, double-label indirect immunostaining was performed with antibodies to m-Msi-1 and to a cell-type specific marker protein, including the Hu proteins HuD (Szabo et al, 1991), HuC (Liu et al, 1995), and HelN-1 (Levine et al, 1993), which label immature and differentiated neurons, C N Pase for myelinating and nonmyelinating differentiated oligodendrocytes (Sprinkle, 1989), and GFAP for astrocytes. GFAP is an intermediate filament that is specifically expressed in mature astrocytes (Bignami and Dahl, 1974).…”

Section: M-msi-1 Expression In the Svz Of The Forebrainmentioning

confidence: 99%

Expression of Neural RNA-Binding Proteins in the Postnatal CNS: Implications of Their Roles in Neuronal and Glial Cell Development

1997

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There is an increasing interest in the role of RNA-binding proteins during neural development. Mouse-Musashi-1 (m-Msi-1) is a mouse neural RNA-binding protein with sequence similarity to Drosophila musashi (d-msi), which is essential for neural development. m-Msi-1 is highly enriched in neural precursor cells that are capable of generating both neurons and glia during embryonic CNS development. The present study characterized m-Msi-1-expressing cells in the postnatal and adult CNS. Postnatally, m-Msi-1 was expressed in proliferative neuronal precursors in the external granule cell layer of the cerebellum and in the anterior corner of the subventricular zone of the lateral ventricles. In gliogenesis, the persistent expression of m-Msi-1 was observed in cells of the astrocyte lineage ranging from proliferative glial precursors in the subventricular zone (SVZ) to differentiated astrocytes in the parenchyma. In addition, we showed that m-Msi-1 was still expressed in proliferating cells in the adult SVZ, which may contain neural precursor or stem cells. Another neural RNA-binding protein Hu (the mammalian homolog of a Drosophila neuronal RNAbinding protein Elav) was present in postmitotic neurons throughout the development of the CNS, and its pattern of expression was compared with that of m-Msi-1. These observations imply that these two RNA-binding proteins may be involved in the development of neurons and glia by regulating gene expression at the post-transcriptional level. Key words: RNA-binding proteins; postnatal CNS; mouseMusashi-1 (m-Msi-1); Hu; Drosophila musashi; neuronal and glial precursor cells; astrocyte lineageA number of transcription factors that f unction in the proliferation and differentiation of neural precursor cells have been identified. However, the recent discovery of neural-specific RNAbinding proteins raises the possibility that the development of neural cells from the precursors may also be regulated at the post-transcriptional level. We believe that at least two gene families are represented by the neural RNA-binding proteins found in both invertebrates and vertebrates (Okano, 1995;Sakakibara et al., 1996). One, the Elav family, includes Drosophila elav genes (Yao et al., 1993) and their mammalian homologs, the Hu genes (Szabo et al., 1991). Members of this family share extensive sequence similarity with one another, and they seem to be expressed mainly in postmitotic neurons (Okano and Darnell, 1997). The other Msi family is composed of Drosophila musashi (Nakamura et al., 1994), Xenopus laevis nrp-1 (Richter et al., 1990), and their mouse homolog mouse-musashi-1 (m-msi-1) (Sakakibara et al., 1996). d-Msi is required for the two successive asymmetric cell divisions of sensory organ precursors (Nakamura et al., 1994). In contrast to the Elav family, the members of the Msi family are expressed in the neural precursor cells at least during embryonic C NS development (Sakakibara et al., 1996). Although the molecular f unctions and the in vivo RNA targets of Msi and Elav families remain largel...

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Paraneoplastic Encephalomyelitis Antigens Bind to the AU-rich Elements of mRNA

Cited by 120 publications

References 14 publications

Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA

Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA

HuD, a Neuronal-specific RNA-binding Protein, Increases thein Vivo Stability of MYCN RNA

Expression of Neural RNA-Binding Proteins in the Postnatal CNS: Implications of Their Roles in Neuronal and Glial Cell Development

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