Superinduction of human interleukin-2 messenger RNA by inhibitors of translation

Efrat, Shimon; Zelig, Silviu; Yagen, Boris; Kaempfer, Raymond

doi:10.1016/0006-291x(84)90307-3

Cited by 45 publications

(17 citation statements)

References 15 publications

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“…Subsequent to the induction phase, accumulation of IL-2 mRNA is promptly "downregulated" or shut off (7). This downregulation requires the synthesis of a short-lived "protein repressor" whose production can be prevented by CHX and other inhibitors of protein synthesis (7,8). Inhibition of this labile "repressor" by treatment with CHX leads to a superinduction of IL-2 mRNA and lymphokine production by lymphocytes (7 this previously postulated protein repressor (7,8) is probably a labile nuclease(s) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Regulation of IL-2 production in vivo by activated T-helper lymphocytes appears to be controlled at both the transcriptional and posttranscriptional levels (6)(7)(8)13). Activation of lymphocytes by mitogens, phorbol esters, or both greatly increases the levels of IL-2 mRNA as a result of de novo gene transcription (6,30).…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate the inability of recipient bovine lymphoid cells to express CAT-fusion genes containing inserted (TATT)" repeat sequences in their 3'-UTRs, we attempted to overcome this blockage by treatment of the transfected lymphoid cells with CHX, a compound that inhibits translation by interfering with peptide bond formation. Appropriate treatment of activated human lymphocytes with CHX is known to result in "superinduction" of both IL-2 mRNA and secreted IL-2 protein (7,8). CHX also induces the production of human /3-interferon in normally nonproducing mouse NIH 3T3 cells transfected with the human /-interferon gene (5).…”

Section: Methodsmentioning

confidence: 99%

“…In the case of superinduction of IL-2 by CHX treatment in human lymphocytes, it has been postulated that a short-lived protein "repressor" molecule whose synthesis is prevented by exposure to the drug might be involved (7). This repressor most likely operates at a posttranscriptional level (7,8). Effects of CHX on posttranscriptional processes during the induction of human /3-interferon (2-4), human y-interferon (5), and human granulocyte/macrophage colony-stimulating factor (15) have also recently been reported.…”

Section: Methodsmentioning

confidence: 99%

“…These results suggest a complex in vivo role for the 3'-UTR of bIL-2 cDNA and the conserved (TATT)n sequences found within it. They also offer a plausible explanation for the high degree of conservation of similar A+T-rich sequences in the 3'-UTRs of many of the other immuneresponse and growth-regulatory genes of mammals.A common control feature shared by many lymphokine, cytokine, growth-factor, and immune-response genes of mammals is the dual operation of both transcriptional and posttranscriptional mechanisms to regulate their expression in vivo (1)(2)(3)(4)(5)(6)(7)(8). From detailed analyses of the cDNAs and genomic molecular clones coding for some of these genes, certain of the DNA sequences involved in the cell-specific inducible promotion (9-11) and enhancement (12) of transcription, as well as sequences involved in posttranscriptional processes (2,5,(13)(14)(15), have been identified.…”

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confidence: 99%

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Posttranscriptional gene regulation and specific binding of the nonhistone protein HMG-I by the 3' untranslated region of bovine interleukin 2 cDNA.

Reeves¹,

Elton²,

Nissen³

et al. 1987

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

120

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The 3' untranslated tail region (3'-UTR) of the cDNA of bovine interleukin 2 (bIL-2) acts as a lymphoid cell-specific gene regulatory element in vivo when ligated to the 3' end of the "marker" bacterial gene coding for chloramphenicol acetyltransferase (CAT) and the hybrid fusion gene is introduced into bovine lymphoid cells by transfection. Evidence is also presented that the 3'-UTR with its conserved (TATT). motif probably has multiple functions in lymphoid cells operating both at the chromosomal level, where the sequence may be involved in the specific binding of the nonhistone chromatin high mobility group protein HMG-I, and at the RNA level, where the conserved sequence is involved in selective posttranscriptional mRNA degradation by a lymphocyte-specific nuclease(s). These results suggest a complex in vivo role for the 3'-UTR of bIL-2 cDNA and the conserved (TATT)n sequences found within it. They also offer a plausible explanation for the high degree of conservation of similar A+T-rich sequences in the 3'-UTRs of many of the other immuneresponse and growth-regulatory genes of mammals.A common control feature shared by many lymphokine, cytokine, growth-factor, and immune-response genes of mammals is the dual operation of both transcriptional and posttranscriptional mechanisms to regulate their expression in vivo (1)(2)(3)(4)(5)(6)(7)(8). From detailed analyses of the cDNAs and genomic molecular clones coding for some of these genes, certain of the DNA sequences involved in the cell-specific inducible promotion (9-11) and enhancement (12) of transcription, as well as sequences involved in posttranscriptional processes (2,5,(13)(14)(15), have been identified. In this regard we (13), and others (14, 15), have recently identified long stretches (>20 nucleotides) of a highly conserved A+U-rich sequence commonly found in the 3' untranslated tail region (3'-UTR), between the termination codon and the polyadenylylation signal, of the mRNAs of many of the known lymphokine, cytokine, and protoonco-genes. At the DNA level this conserved sequence appears to be composed of tandem repeats of an ancestral tetranucleotide (TATT) unit that has undergone limited divergence during the evolution of these genes (13). Significantly, not all of the genes known to be induced during the immune activation of lymphocytes [e.g., the interleukin-2 (IL-2) receptor (16), the transferrin receptor (17), and certain proteases (18)] have such canonical sequence motifs in their 3'-UTRs, suggesting that these highly conserved (TATT)n sequences may serve specific regulatory or other roles in those genes that do possess them. Here we report on multiple functions found to be associated with the 3'-UTR ofthe cDNA of bovine interleukin-2 (bIL-2). MATERIALS AND METHODSCell Culture and DNA Transfections. Adherent strains of IL-2-dependent bovine lymphoid cells (e.g., E3 and 27X) were derived and maintained as previously described (13) 6531The publication costs of this article were defrayed in part by page charge payment. This article must t...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Posttranscriptional gene regulation and specific binding of the nonhistone protein HMG-I by the 3' untranslated region of bovine interleukin 2 cDNA.

Reeves¹,

Elton²,

Nissen³

et al. 1987

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

120

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Activation of lymphokine genes during stimulation of cloned T cells

et al. 1986

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To study the regulation of lymphokine production by T lymphocytes, we have characterized the activation of lymphokine genes in T cells by measuring the levels of lymphokine mRNA in cloned murine T lymphocytes after stimulation. Lymphokine mRNA was not detected in cells taken after seven days of maintenance culture. Following stimulation of T helper lymphocytes L2 and AD9.1 with concanavalin A, lymphokine mRNA appeared, reached peak levels and disappeared over a 43-h time period. A single stimulation event resulted in the induction of mRNA for interleukin 2 (IL 2), IL 3 and interferon gamma. Maximal mRNA levels were generally found at 6 h in the T helper lymphocytes, but could occur as late as 18 h. The lymphokine genes were expressed coordinately; however, in these cloned cells, IL 2 mRNA levels appeared to be lower than the other two mRNAs. Lymphokine titers in the supernatant fluids paralleled the appearance of mRNA but IL 2 titers began to fall after 12 h probably because of utilization of this lymphokine by the activated cells. In the cytolytic T lymphocyte, L3, qualitatively similar kinetics were found after stimulation by lectin or a clonotypic antibody with peak mRNA levels occurring later (18 h) with the antibody. These studies indicate a single stimulating event activates the lymphokine genes of T cells in a coordinate manner; the appearance of the lymphokines in supernatant fluids represents de novo synthesis of these proteins but the levels of lymphokines measured in supernatant fluids reflects both production and utilization rates, and exposure to IL 2 at the time of stimulation is not essential for the production of other lymphokines.

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Regulation of lymphokine expression in T cell activation. I. Rapid loss of interleukin‐specific RNA after removal of the stimulating signal

1991

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Resting T lymphocytes can be induced to express a variety of lymphokines after antigenic or mitogenic stimulation. Expression is regulated both at the transcriptional level, through induction of T cell-specific DNA-binding proteins, and at the post-transcriptional level through alteration of precursors or mRNA stability. To investigate whether lymphokine expression follows a preprogrammed course after activation of T cells or whether it is dependent on the continued monitoring of activating signals, we followed the fate of interleukin (IL) 2, IL 4 and IL 2 receptor mRNA after removal of the stimulating signal concanavalin (Con A) by alpha-methylmannoside (alpha MM). IL 2 and IL 4 needed continued stimulation of the cells for RNA expression, as shown by the rapid disappearance of IL 2 and IL 4 mRNA after addition of alpha MM to stimulated cells, while IL 2 receptor mRNA which is also induced after Con A stimulation was minimally influenced. In the case of both IL no new mature mRNA was generated after removal of the stimulating signal. The T1/2 of IL 2 mRNA remained unchanged after alpha MM treatment as compared to actinomycin D treatment, while IL 4 mRNA became labilized after withdrawal of the signal.

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Superinduction of human interleukin-2 messenger RNA by inhibitors of translation

Cited by 45 publications

References 15 publications

Posttranscriptional gene regulation and specific binding of the nonhistone protein HMG-I by the 3' untranslated region of bovine interleukin 2 cDNA.

Posttranscriptional gene regulation and specific binding of the nonhistone protein HMG-I by the 3' untranslated region of bovine interleukin 2 cDNA.

Activation of lymphokine genes during stimulation of cloned T cells

Regulation of lymphokine expression in T cell activation. I. Rapid loss of interleukin‐specific RNA after removal of the stimulating signal

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