The 3' untranslated region of the human interferon-beta mRNA has an inhibitory effect on translation.

Kruys, Véronique; Wathelet, Marc; Poupart, P.; Contreras, Roland; Fiers, Walter; Huez, Georges

doi:10.1073/pnas.84.17.6030

Cited by 161 publications

(90 citation statements)

References 22 publications

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“…The antisense-induced deficiency in prothymosin a, relative to other acidic proteins viewed in two-dimensional gels, corroborates this conclusion. The results also suggest that sequences at the 3' ends of mRNA are important for translation (17), an observation made previously with antisense RNA transcripts complementary to the entire 3'-noncoding region of creatine kinase mRNA (18). The uptake and stability of the oligomers were measured by using [32P]DNA molecules.…”

Section: Discussionmentioning

confidence: 99%

Prothymosin alpha antisense oligomers inhibit myeloma cell division.

Sburlati

Manrow²,

Berger³

1991

Proc. Natl. Acad. Sci. U.S.A.

147

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The function of prothymosin a has been investigated by using four different antisense oligodeoxyribonucleotides directed at selected regions of its mRNA. In every case, when synchronized human myeloma cells were released from stationary phase by incubation in fresh medium containing antisense oligomers, cell division was prevented or inhibited; sense oligomers and random antisense oligomers had no effect. A detailed analysis of synchronized cell populations indicated that sense-treated and untreated cells divided m17 hr after growth initiation, whereas cells incubated with antisense oligomer 183, a 16-mer targeted 5 bases downstream of the initiation codon, entered mitosis approximately one cell division late. The failure to divide correlated directly with a deficit in prothymosin a and with the continued presence of intact intracellular antisense oligomers over a period ofat least 24 hr. Because antisense oligomers had no effect either on the timing of the induction of prothymosin a mRNA upon growth stimulation or on mRNA levels seen throughout the cell cycle, we concluded that antisense DNA caused specific hybrid arrest of translation. Our data suggest that prothymosin a is required for cell division. However, there is no evidence that prothymosin a directly regulates mitosis.The function of prothymosin a is debatable. Evidence from this and other laboratories suggests that the protein is neither a precursor of thymosin a,, a putative thymic hormone, nor a secreted thymic hormone itself (1-3). Instead, several observations support a role in cell proliferation: (i) Prothymosin a mRNA and protein are present in virtually all mammalian tissues, and a homologous protein has been detected in yeast (1,(4)(5)(6)(7)(8); these findings are consistent with an activity essential to most cells. (ii) The amounts of prothymosin a and its mRNA are roughly proportional to the proliferative activity of the tissue from which they are isolated (1,4,7). (iii) Prothymosin a mRNA is induced in normal human lymphocytes and in serum-starved NIH 3T3 cells upon growth stimulation with mitogens or serum, respectively (1).Using COS cells transfected with the human prothymosin a gene, we have recently shown that prothymosin a is a nuclear protein. We have also found that chimeric proteins composed of all or part of prothymosin a fused with (3-galactosidase are targeted to the nucleus only when the basic amino acids at the carboxyl terminus of prothymosin a are included (9). The presence of a nuclear localization signal indicates a function carried out, at least in part, in the nucleus; the precise nature of that function is unknown.In the present study, we have directly evaluated the relationship between prothymosin a and cell division. Using antisense oligomers to inhibit accumulation ofprothymosin a in a synchronized population of myeloma cells, we have established that cells deficient in prothymosin a cannot divide, that the inhibition is reversible, and that degradation of intracellular antisense oligomers accompanies resumpti...

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Section: Discussionmentioning

confidence: 99%

Prothymosin alpha antisense oligomers inhibit myeloma cell division.

Sburlati

Manrow²,

Berger³

1991

Proc. Natl. Acad. Sci. U.S.A.

147

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“…Indeed, these AU-rich sequences are found in mRNAs of cytokines, oncogenes, transcription factors, and primary response genes (51,67) and are implicated in mediating the degradation of mRNA (51,68) and regulating the efficiency of translation (69,70).…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Characterization of a Novel Mouse Macrophage Gene That Encodes a Nuclear Protein Comprising Polyglutamine Repeats and Interspersing Histidines

Cox

Taylor

Willis

et al. 1996

Journal of Biological Chemistry

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Simple tandem repeats of the trinucleotide sequence CAG encode homopolymeric stretches of glutamine. Although polyglutamine has been identified in diverse proteins, it is present predominantly in transcription factors. We observed that oncogene-immortalized mouse macrophages express several genes that contain a CAG repeat motif. Therefore, we attempted to clone a novel gene that contains a CAG repeat and is associated with cytokine activation of macrophages. Screening of a mouse macrophage cDNA library with a probe comprising 12 consecutive CAG triplets identified at least one unique clone. The cDNA encodes a protein (named GRP-1 or glutamine repeat protein-1) with 171 amino acids, a calculated molecular mass of 21.6 kDa, and a predicted pI of 10.67. Greater than two-thirds of GRP-1 are only two amino acids, namely glutamine (50%) and histidine (18%). There are four polyglutamine motifs interspersed with histidine-rich regions. There is also a putative nuclear localization signal flanked by sites for possible serine phosphorylation. GRP-1 mRNA was expressed constitutively in some macrophage cell lines and B and T cell lines. Interferon-␥ or lipopolysaccharide augmented GRP-1 mRNA expression in the mouse macrophage cell line ANA-1. Western blot analyses using an antipeptide serum revealed that GRP-1 was localized in the nucleus of ANA-1 macrophages and transfected 3T3 fibroblasts. Overexpression of GRP-1 decreased Sp1-driven chloramphenicol acetyltransferase gene expression in transient cotransfection experiments. Because polyglutamine motifs can cause protein oligomerization and can function as transcriptional activation domains, we suggest that GRP-1 may be a transcription factor associated with interferon-␥-or lipopolysaccharide-induced activation of macrophages.Macrophages play a major role in the immune system through numerous activities expressed either constitutively or after exposure to cytokines, bacterial lipopolysaccharide (LPS) 1 or other agents either alone or in combination (1). For example, macrophages affect T-cell activation by processing and presenting antigens, and they promote inflammatory reactions by secreting various cytokines. In addition, activated macrophages exert potent antibacterial, antiviral, and antitumor functions.To avoid the difficulties associated with isolating large homogeneous populations of macrophages for studying such functions, several oncogene-immortalized mouse macrophage cell lines were generated that emulate normal tissue macrophages (2-4). Although these and other macrophage populations do not synthesize and secrete IL-2, Northern blot analyses revealed the expression of several genes in oncogene-immortalized macrophages that were at least partially homologous with mouse IL-2 cDNA. The expression of at least one of these genes was regulated by IFN-␥ and/or LPS. Subsequent experiments showed that these macrophage genes were homologous with sequences contained in exon I of the mouse IL-2 gene. 2 This region is particularly noteworthy because it contains a tandem repea...

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“…A role of the 3′untranslated region (3′UTR) has been demonstrated by showing that the IFN-β 3′UTR has an inhibitory effect on the translation of IFN-β or Xenopus beta globin [11]; likewise, the murine IFN-α 3′UTR also has an inhibitory effect on translation of beta globin mRNA [12]. The translation inhibitory action of the IFN-β 3′UTR is thought to be mediated by interactions of adenylate uridylate (AU)-rich elements (AREs) and the polyA tail, since the removal of either region improves translation efficiency [13].…”

Section: Post-transcriptional Regulation Of Ifn-beta: the "Super-indumentioning

confidence: 99%

Post-transcriptional control of the interferon system

Khabar

Young

2007

Biochimie

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The interferon (IFN) system is a well-controlled network of signaling, transcriptional, and posttranscriptional processes that orchestrate host defense against microbes. The IFN response comprises a multi-array of IFN-stimulated gene products that mediate a variety of biological processes designed to control infection and regulate specific immune responses. In this review, we focus on posttranscriptional mechanisms of gene regulation that occur during the course of IFN induction and during the response of cells to IFN. Post-transcriptional mechanisms involve different levels of regulation such as mRNA stability, alternative splicing, and translation. Such controls offer a fine tuning mechanism for efficient and rapid response and as a negative feedback control in IFN biosynthesis and response.

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The 3' untranslated region of the human interferon-beta mRNA has an inhibitory effect on translation.

Abstract: In vitro-transcribed human interferon-I3

Cited by 161 publications

References 22 publications

Prothymosin alpha antisense oligomers inhibit myeloma cell division.

Prothymosin alpha antisense oligomers inhibit myeloma cell division.

Molecular Cloning and Characterization of a Novel Mouse Macrophage Gene That Encodes a Nuclear Protein Comprising Polyglutamine Repeats and Interspersing Histidines

Post-transcriptional control of the interferon system

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