Translation of 15-lipoxygenase mRNA is inhibited by a protein that binds to a repeated sequence in the 3′ untranslated region.

Ostareck-Lederer, Antje; Ostareck, Dirk H.; Standart, Nancy; Thiele, B

doi:10.1002/j.1460-2075.1994.tb06402.x

Cited by 251 publications

(171 citation statements)

References 40 publications

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“…26 Indeed, a scan of the D4 sequence for sequences that may modify RNA stability and translational efficiency 27 identified hnRNP K and E binding sites, known as DICE, that are present as a tandem repeated sequence in the 15-lipoxygenase 3 0 untranslated region and suppress translation. 28,29 This identified consensus sequence is present in the region analyzed and includes sequences in the first repeat unit (a sequence). The observation that the single-stranded sense strand of the repeat 72 bp sequence, but not the antisense strand, could block the mobility shift of the nuclear factor (not shown) is consistent with this finding because KH domain proteins, like hnRNP K, can bind to single-stranded DNA with a similar specificity as to their RNA targets.…”

Section: O Schoots and Hhm Van Tolmentioning

confidence: 99%

The human dopamine D4 receptor repeat sequences modulate expression

2003

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Genetic studies have implicated a polymorphic repeat sequence in exon 3 of the human dopamine D4 receptor in various behavioral and psychiatric disorders. Functionally various repeat variants are nearly identical, but whether these have different effects on gene expression has not been studied. To study the role of the repeat sequences on expression independently from its structural and functional effects at the protein level, we introduced these sequences immediately upstream of the promoter and in the 3 0 untranslated region of a luciferase reporter vector. In this report, we demonstrate that the repeat sequence can both modulate promoter activity and alter expression post-transcriptionally. The repeat sequence can serve as a substrate for a nuclear binding factor and all the three repeat variants can suppress promoter activity. Placement of the three repeat variants downstream from the luciferase gene in the expression vector shows, however, that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats, likely via mechanisms involving RNA stability or translational efficiency. These data indicate that the various D4 repeat sequences have different effects on expression, which may explain its potential role in behavioral disorders.

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Section: O Schoots and Hhm Van Tolmentioning

confidence: 99%

The human dopamine D4 receptor repeat sequences modulate expression

2003

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“…R15-LOX mRNA, highly abundant already in the normoblast stages, is translationally silenced until enucleated reticulocytes in the peripheral blood are matured. The r15-LOX mRNA 3' untranslated region (3'UTR) bears a repetitive CU-rich sequence (Fleming et al, 1989) which we termed the differentiation control element (DICE) (Ostareck-Lederer et al, 1994, Ostareck et al, 1997. HnRNP K and hnRNP E1 specifically bind to the DICE.…”

Section: Regulation Of R15-lox Mrna Translation During Erythroid Cellmentioning

confidence: 99%

Control of mRNA translation and stability in haematopoietic cells: The function of hnRNPs K and E1/E2

Ostareck-Lederer

Ostareck

2004

Biology of the Cell

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Studies on the post-transcriptional regulation of gene expression in haematopoietic cells have uncovered that a subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs) is involved in cytoplasmic gene regulation. HnRNP K and hnRNP E1/E2 share a common structural motif, the hnRNP K homology (KH) domain, which provides a structural basis for mRNA binding. The KH-domains are components of a modular system, which enables these proteins to engage in both, protein/nucleic acid and protein/protein interactions, the latter generating connectivity to cell signalling events. As components of different mRNA-protein complexes, hnRNP K and hnRNP E1/E2 function in the control of mRNA translation and mRNA stability in haematopoietic cell differentiation.

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“…Other studies have also shown that the 3h-UTR can influence the efficiency of protein translation independently of polyadenylation. For example, a specific mRNA binding protein of 48 kDa has been identified that binds to the 3h-UTR of the 15-lipoxygenase mRNA, to inhibit its translation, suggesting that the 3h-UTR regulates translation [9]. Thus, control of cell function by the 3h-UTR appears to occur at multiple levels and recent interest has focused on identifying sequences and motifs within the 3h-UTR, as well as in the binding proteins that recognize them.…”

Section: Introductionmentioning

confidence: 99%

Functional role for the angiotensin II receptor (AT1A) 3′-untranslated region in determining cellular responses to agonist: evidence for recognition by RNA binding proteins

Thekkumkara

Gruber

Motel

et al. 1998

Biochemical Journal

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We demonstrate a functional role for the 3ʹ-untranslated region (3ʹ-UTR) of the angiotensin II (Ang II) receptor subtype AT1A mRNA in Chinese hamster ovary (CHO-K1) cells by stably transfecting the coding region of the receptor gene with or without the 845 bp 3ʹ-UTR. Two cell lines expressing similar levels of cell-surface receptors (with 3ʹ-UTR, Bmax = 571 fmol/mg protein; without 3ʹ-UTR, Bmax = 663 fmol/mg protein) were used in the present study. Both cell lines expressed high-affinity receptors (with 3ʹ-UTR, Kd = 0.83 nM; without 3ʹ-UTR, Kd = 0.82 nM), and binding studies with 125I-labelled Ang II in the presence of GTP[S] demonstrated that both coupled to heterotrimeric G-proteins. Despite these similarities, significant differences were observed for receptor-mediated cell signalling pathways. In cells without the 3ʹ-UTR, Ang II stimulated an increase in cAMP accumulation (11-fold above control) and in cells with the 3ʹ-UTR no stimulation was observed, which was consistent with previous observations in most endogenous Ang II receptor (AT1)-expressing cells. Activation of cAMP by Ang II in cells without the 3ʹ-UTR correlated with an inhibition of DNA synthesis, determined by [3H]thymidine incorporation. Ang II-mediated responses were blocked by EXP3174, a selective non-peptide receptor antagonist. We also observed differences in the transient profiles of intracellular calcium between cells with and without the 3ʹ-UTR in response to Ang II. In cells with the 3ʹ-UTR, a sustained level of intracellular calcium was observed after Ang II stimulation, whereas cells without the 3ʹ-UTR displayed a full return to basal level within 50 s of Ang II treatment. Even though the expressed exogenous gene is under the control of a constitutively expressing promoter (cytomegalovirus promoter), Northern-blot analysis revealed a considerably greater accumulation of AT1A mRNA in cells without the 3ʹ-UTR compared with cells with the 3ʹ-UTR. Analysis of the decay rate of the AT1A mRNA in cells with and without the 3ʹ-UTR revealed that the normally unstable AT1A receptor mRNA became highly stable by removing its 3ʹ-UTR, identifying a role for the 3ʹ-UTR in mRNA destabilization. Interestingly, both cells express similar levels of receptors at the cell surface, suggesting that the 3ʹ-UTR is also involved in the efficient translation and/or translocation of the receptor protein to the plasma membrane. We hypothesized that these 3ʹ-UTR-mediated functions of the receptor are regulated by RNA-binding proteins. To identify possible RNA-binding proteins for the AT1A 3ʹ-UTR, cellular extracts were prepared from parental CHO-K1 cells and 3ʹ-UTR-binding assays, electrophoretic mobility-shift assays and UV crosslinking studies were performed. A major cellular protein of 55 kDa was identified, which specifically interacted with the 3ʹ-UTR. Our data suggest that the 3ʹ-UTR of the AT1A can control specific receptor functions, perhaps via selective recognition of the 3ʹ-UTR by RNA-binding proteins.

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Translation of 15-lipoxygenase mRNA is inhibited by a protein that binds to a repeated sequence in the 3′ untranslated region.

Cited by 251 publications

References 40 publications

The human dopamine D4 receptor repeat sequences modulate expression

The human dopamine D4 receptor repeat sequences modulate expression

Control of mRNA translation and stability in haematopoietic cells: The function of hnRNPs K and E1/E2

Functional role for the angiotensin II receptor (AT1A) 3′-untranslated region in determining cellular responses to agonist: evidence for recognition by RNA binding proteins

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