Differential mRNA stability to reticulocyte ribonucleases correlates with 3′ non‐coding (U)<sub><i>n</i></sub>A sequences

Wreschner, Daniel H.; Rechavi, Gideon

doi:10.1111/j.1432-1033.1988.tb13891.x

Cited by 77 publications

(28 citation statements)

References 47 publications

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“…Translational readthrough might dislodge such a factor or expose a target site, leading to accelerated metabolism of the CS message. Several reports have indicated that erythroid cells have degradation pathways which show a preference for particular mRNAs or sequences (4,30,31,37,61). Tissuespecific RNases may be particularly relevant to the erythroid lineage, where substantial mRNA turnover accompanies RBC differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Although some progress has been made in identifying potential cis-acting RNA elements, trans-acting proteins, and nucleases involved in mRNA degradation in the RBC (4,30,31,35,49,61), the bases for the longevities of globin mRNAs and for the degradation of nonglobin mRNAs during RBC differentiation are presently undefined. We have initiated studies to explore the mechanisms which regulate a-globin mRNA stability by examining the defect in expression of a naturally occurring ot2-globin mutation, ot2Constant Spring (CS).…”

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confidence: 99%

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Erythroid cell-specific determinants of alpha-globin mRNA stability.

1994

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Although globin mRNAs are considered prototypes of highly stable messages, the mechanisms responsible for their longevity remain largely undefined. As an initial step in identifying potential cis-acting elements or structures which contribute to their stability, we analyzed the defect in expression of a naturally occurring a2-globin mutant, aConstant Spring (CS). The CS mutation is a single-base change in the translation termination codon (I!AA-WCAA) that allows the ribosome to read through into the 3' nontranslated region (NTR). The presence of CS mRNA in transcriptionally active erythroid precursors and its absence (relative to normal a-globin mRNA) in the more differentiated transcriptionally silent erythrocytes suggest that this mutation disrupts some feature of the a-globin mRNA required for its stability. Using a transient transfection system, we demonstrate that in murine erythroleukemia cells the CS mRNA is unstable compared with the normal a2-globin mRNA. The analyses of several other naturally occurring and site-directed mutant a-globin genes in murine erythroleukemia cells indicate that entry of a translating ribosome into the 3' NTR targets the message for accelerated degradation in erythroid cells. In contrast, both the CS and a2-globin mRNAs are stable in several nonerythroid cell lines. These results suggest that translational readthrough disrupts a determinant associated with the a2-globin 3' NTR which is required for mRNA stability in erythroid cells.While the major roles of transcription and processing in the control of gene expression have long been acknowledged (13), a number of systems which demonstrate a primary role for regulation at the level of mRNA stability have recently been described (reviewed in references 2, 7, 42, and 44). In eucaryotes, mRNAs have a wide range of half-lives, from as short as a few minutes to as long as several days. These differences in mRNA stability can have significant impacts on the levels of gene expression (20,48). A variety of elements and mechanisms appear to be responsible for modulating mRNA halflives. Features governing the turnover of individual mRNAs have been attributed to specific cis-acting RNA sequences and structures and to trans-acting proteins (10,27,36,41,45,46,55,57,63). An additional level of complexity is possible as an mRNA is translated, since the interaction of cis-and transacting elements with the ribosome and its associated components or with higher-order RNA structures could modulate mRNA turnover (47,52).The at-and P-globin gene clusters are useful model systems to study mechanisms responsible for mRNA stability. Globin genes are expressed in highly specialized, terminally differentiated erythrocytes (RBC) and can account for as much as 95% of the soluble proteins (17,43). During RBC differentiation the nucleus is extruded (17) and globin mRNAs increase from less than 1% to more than 98% of the total mRNA (6). This high-level accumulation of globin mRNA is dependent not only on increased transcription but also on the long half-lives...

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Section: Discussionmentioning

confidence: 99%

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Erythroid cell-specific determinants of alpha-globin mRNA stability.

1994

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“…There is some evidence suggesting that the stabilities of globin mRNAs may be mediated by cis-acting elements (25,44,53) or structural alterations in the message (34). Additional studies demonstrate that erythroid cells have degradation pathways which preferentially act on certain sequences or mRNAs (3,29,30,56).…”

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Erythroid Cell-Specific mRNA Stability Elements in the α2-Globin 39 Nontranslated Region

Weiss

Liebhaber

1995

Molecular and Cellular Biology

161

163

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Very little is known about the mechanisms mediating longevities of mRNAs. As a means of identifying potential cis-and trans-acting elements which stabilize an individual mRNA, naturally occurring mutations that decreased stability of the normally long-lived globin mRNA were analyzed. Our previous studies demonstrated that a subset of mutations which allowed the translating ribosome to read through into the ␣2-globin 3 nontranslated region (NTR) targeted the mutant mRNAs for accelerated turnover in erythroid cells but not in several nonerythroid cell lines (I. M. Weiss and S. A. Liebhaber, Mol. Cell. Biol. 14:8123-8132, 1994). These results suggested that translational readthrough interfered with some feature of the ␣2-globin 3 NTR required for message stability in erythroid cells. To define the cis-acting sequences which comprise this erythroid cell-specific stability determinant, scanning mutagenesis was performed on the ␣2-globin 3 NTR, and the stability of each mutant mRNA was examined during transient expression. Three cytidine-rich regions which are required for longevity of the ␣2-globin mRNA were identified. However, in contrast to the readthrough mutations, base substitutions in these elements destabilize the message through a translation-independent mechanism. To account for these results, we propose that the cis-acting elements form a complex or determinant in the normal ␣2-globin mRNA which protects the message from degradation in erythroid cells. Disruption of this determinant, by translational readthrough or because mutations in an element prevent or inhibit its formation, targets the message for accelerated turnover in these cells.

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“…A role for such AU-rich elements (AREs) in influencing mRNA stability has been proposed (Shaw & Kamen 1986, Sachs 1993, with recent work indicating that the AUUUA sequence may form a necessary but not sufficient core sequence that destabilizes some mRNAs (Zubiaga et al 1995, Lagnado et al 1994. It has been noted previously that the prevalence of (U) n A sequences, a possible indicator of mRNA stability, suggested that the porcine, human, bovine and equine gonadotrophin -subunit transcripts may be less stable than those of rat and mouse (Wreschner & Rechavi 1988, Hirai et al 1989.…”

Section: Discussionmentioning

confidence: 99%

The Australian brushtail possum (Trichosurus vulpecula) gonadotrophin alpha-subunit: analysis of cDNA sequence and pattern of expression

Fidler

Lawrence²,

Vanmontfort³

et al. 1998

Journal of Molecular Endocrinology

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A cDNA sequence from the gonadotrophin -subunit mRNA of Australian brushtail possum (Trichosurus vulpecula) has been determined and analysed. Comparison with seven eutherian mammalian gonadotrophin -subunit gene sequences revealed an average of 82·6% homology between the coding region nucleotide sequences and 88·8% identity between the predicted amino acid sequences. The predicted possum gonadotrophin -subunit protein has ten evolutionarily conserved cysteine residues, two potential N-linked glycosylation sites and a putative enzyme recognition sequence which it has been suggested is required for sulphation of carbohydrate moieties. Comparison of the possum gonadotrophin -subunit 3 untranslated region (UTR) sequence with the 3 UTRs of eutherian -subunit transcripts revealed sequence homology. In particular, an 18 nucleotide imperfect palindromic sequence present in the possum 3 UTR, with the potential to form a hairpin loop, was found to be evolutionarily conserved and present in five out of seven eutherian -subunit 3 UTR sequences. In situ hybridization localized the transcripts to a sub-population of anterior pituitary cells presumed to be gonadotrophs and thyrotrophs. In summary, these results indicate considerable conservation of the structure and function of the gonadotrophin -subunit protein since the divergence of the marsupial and eutherian mammalian lineages.

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Differential mRNA stability to reticulocyte ribonucleases correlates with 3′ non‐coding (U)_nA sequences

Cited by 77 publications

References 47 publications

Erythroid cell-specific determinants of alpha-globin mRNA stability.

Erythroid cell-specific determinants of alpha-globin mRNA stability.

Erythroid Cell-Specific mRNA Stability Elements in the α2-Globin 39 Nontranslated Region

The Australian brushtail possum (Trichosurus vulpecula) gonadotrophin alpha-subunit: analysis of cDNA sequence and pattern of expression

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Differential mRNA stability to reticulocyte ribonucleases correlates with 3′ non‐coding (U)nA sequences

Cited by 77 publications

References 47 publications

Erythroid cell-specific determinants of alpha-globin mRNA stability.

Erythroid cell-specific determinants of alpha-globin mRNA stability.

Erythroid Cell-Specific mRNA Stability Elements in the α2-Globin 39 Nontranslated Region

The Australian brushtail possum (Trichosurus vulpecula) gonadotrophin alpha-subunit: analysis of cDNA sequence and pattern of expression

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Differential mRNA stability to reticulocyte ribonucleases correlates with 3′ non‐coding (U)_nA sequences