Cyclosporin A inhibits growth of autocrine tumour cell lines by destabilizing interleukin-3 mRNA

Nair, Asha P. K.; Hahn, Sinuhe; Banholzer, Rolf; Hirsch, Hans H.; Moroni, Christoph

doi:10.1038/369239a0

Cited by 104 publications

(94 citation statements)

References 27 publications

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“…Of course, we cannot rule out the possibility that within these AU-rich regions there exist novel determinants of mRNA decay that are at least somewhat distinct from the UUAUUUAUU nonamer with regard to both their sequence and their mechanism of action. Consistent with this possibility are previous observations that some AREs are inactive in selected cell lines and that AREs can be differentially regulated in response to par- (27,34,43). However, it is not yet clear whether these cell-state-dependent differences in ARE potency are determined by differences in the ARE sequences themselves or in the sequences that flank the AREs (23).…”

Section: Fig 6 Decay Of B-(auuu)supporting

confidence: 64%

The Nonamer UUAUUUAUU Is the Key AU-Rich Sequence Motif That Mediates mRNA Degradation

Zubiaga

Belasco

Greenberg

1995

Molecular and Cellular Biology

492

371

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Labile mRNAs that encode cytokine and immediate-early gene products often contain AU-rich sequences within their 3 untranslated region (UTR). These AU-rich sequences appear to be key determinants of the short half-lives of these mRNAs, although the sequence features of these elements and the mechanism by which they target mRNAs for rapid decay have not been fully defined. We have examined the features of AU-rich elements (AREs) that are crucial for their function as determinants of mRNA instability in mammalian cells by testing the ability of various mutant c-fos AREs and synthetic AREs to direct rapid mRNA deadenylation and decay when inserted within the 3 UTR of the normally stable ␤-globin mRNA. Evidence is presented that the pentamer AUUUA, which previously was suggested to be the minimal determinant of instability present in mammalian AREs, cannot direct rapid mRNA deadenylation and decay. Instead, the nonamer UUAUUUAUU is the elemental AU-rich sequence motif that destabilizes mRNA. Removal of one uridine residue from either end of the nonamer (UUAUUUAU or UAUUUAUU) results in a decrease of potency of the element, while removal of a uridine residue from both ends of the nonamer (UAUUUAU) eliminates detectable destabilizing activity. The inclusion of an additional uridine residue at both ends of the nonamer (UUUAUUUAUUU) does not further increase the efficacy of the element. Taken together, these findings suggest that the nonamer UUAUUUAUU is the minimal AU-rich motif that effectively destabilizes mRNA. Additional ARE potency is achieved by combining multiple copies of this nonamer in a single mRNA 3 UTR. Furthermore, analysis of poly(A) shortening rates for ARE-containing mRNAs reveals that the UUAUUUAUU sequence also accelerates mRNA deadenylation and suggests that the UUAUUUAUU motif targets mRNA for rapid deadenylation as an early step in the mRNA decay process.

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Section: Fig 6 Decay Of B-(auuu)supporting

confidence: 64%

The Nonamer UUAUUUAUU Is the Key AU-Rich Sequence Motif That Mediates mRNA Degradation

Zubiaga

Belasco

Greenberg

1995

Molecular and Cellular Biology

492

371

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“…Consistent with this possibility are previous observations that some AREs are inactive in selected cell lines and that AREs can be differentially regulated in response to particular extracellular stimuli (submitted for publication; Schuler and Cole, 1988;Lindsten et al, 1989;Nair et al, 1994;Schiavone et al, 2000). Several signaling pathways have been implicated in regulating the decay of specific mRNAs.…”

Section: Function-specific Regulationsupporting

confidence: 62%

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Bevilacqua

Ceriani

Capaccioli

et al. 2003

Journal Cellular Physiology

293

259

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Recent evidence suggests that gene expression may be regulated, at least in part, at post-transcriptional level by factors inducing the extremely rapid degradation of messenger RNAs. These factors include reactions between adenyl-uridyl-rich elements (AREs) of the relevant mRNA and either specific proteins that bind to these elements or exosomes. This review deals with examples of the proteins (AU-rich binding proteins, AUBPs) and exosomes, which have been shown to form complexes with AREs and bring about rapid degradation of the relevant mRNA, and with certain other factors, which protect the RNA from such degradation. The biochemical and physiological factors underlying the stability of messenger RNAs carrying the ARE motifs will be reviewed in the light of their emerging significance for cell physiology, human pathology, and molecular medicine. We also consider the possible application of the results of recent insights into the mechanisms to pharmacological interventions to prevent or cure disorders, especially developmental disorders, which the suppression of gene expression may bring about. Molecular targeting of specific steps in protein degradation by synthetic compounds has already been utilized for the development of pharmacological therapies.

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“…Mutations which affect transcript stability can have a very significant impact on regulated gene expression (26,33). The mechanism of regulated turnover of mammalian mRNA, however, is largely unknown.…”

mentioning

confidence: 99%

The Poly(A) Tail Inhibits the Assembly of a 3′-to-5′ Exonuclease in an In Vitro RNA Stability System

Ford

Bagga

Wilusz

1997

Molecular and Cellular Biology

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We have developed an in vitro system which faithfully reproduces several aspects of general mRNA stability. Poly(A) ؊ RNAs were rapidly and efficiently degraded in this system with no detectable intermediates by a highly processive 3 -to-5 exonuclease activity. The addition of a poly(A) tail of at least 30 bases, or a 3 histone stem-loop element, specifically stabilized these transcripts. Stabilization by poly(A) required the interaction of proteins with the poly(A) tail but did not apparently require a 3 OH or interaction with the 5 cap structure. Finally, movement of the poly(A) tract internal to the 3 end caused a loss of its ability to stabilize transcripts incubated in the system but did not affect its ability to interact with poly(A) binding proteins. The requirement for the poly(A) tail to be proximal to the 3 end indicates that it mediates RNA stability by blocking the assembly, but not the action, of an exonuclease involved in RNA degradation in vitro.The relative stability of RNA transcripts plays a key role in determining their steady-state levels as well as the rate of mRNA induction following a transcriptional stimulus (30). Mutations which affect transcript stability can have a very significant impact on regulated gene expression (26,33). The mechanism of regulated turnover of mammalian mRNA, however, is largely unknown. Terminal structures, namely, the 5Ј cap and 3Ј poly(A) tail, serve as general stabilizing elements found on most mRNAs (7,14). Several internal sequences, such as an AU-rich element (10) or nonsense codons (5), which functionally shorten the half-lives (t 1/2 ) of mRNAs have been identified. Furthermore, an internal element which stabilizes ␣ globin mRNA has recently been identified (38). Elucidating how the general and regulatory elements interact to determine the functional t 1/2 of mRNAs is vital to understanding the mechanism of RNA stability as a regulator of gene expression.The poly(A) tail, a posttranscriptional modification of the 3Ј end of all nonhistone mRNAs, is initially formed as a 150-to 200-base homopolymer (19) which assembles multiple molecules of a poly(A) binding protein (PABP) (13). The tail is a dynamic structure which serves as a mediator through which several important cellular processes including the initiation of translation (31), nucleocytoplasmic transport (18), and mRNA stability (7), are regulated. Most mRNAs are rapidly degraded following deadenylation of their 3Ј ends to approximately 30 adenylate residues (8,21,27,34). Many destabilizing elements appear to act by increasing the rate of deadenylation (11). The disruption of poly(A) tail function, therefore, appears to be the rate-limiting step in mRNA turnover. Following deadenylation, mRNA degradation can occur through a variety of exoand/or endonucleolytic pathways (4). The difficulty in identifying intermediates in mammalian mRNA turnover has significantly hindered attempts to probe further into mechanistic aspects of the turnover process.Mechanistic questions in mammalian systems are usually best ...

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Cyclosporin A inhibits growth of autocrine tumour cell lines by destabilizing interleukin-3 mRNA

Cited by 104 publications

References 27 publications

The Nonamer UUAUUUAUU Is the Key AU-Rich Sequence Motif That Mediates mRNA Degradation

The Nonamer UUAUUUAUU Is the Key AU-Rich Sequence Motif That Mediates mRNA Degradation

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

The Poly(A) Tail Inhibits the Assembly of a 3′-to-5′ Exonuclease in an In Vitro RNA Stability System

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