Recombinant interleukin 2 regulates levels of c-myc mRNA in a cloned murine T lymphocyte.

Reed, John C.; Sabath, Daniel E.; Hoover, R G; Prystowsky, Michael B.

doi:10.1128/mcb.5.12.3361

Cited by 71 publications

(37 citation statements)

References 48 publications

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“…Indeed, the IL-2 receptor gene is initially regulated by signals generated several hours before IL-2 secretion is initiated (6; C. D. Pauza and R. C. Holmes, unpublished data). A sharp increase in c-myc gene expression after IL-2 addition was not observed, even though a positive effect of IL-2 addition on c-myc gene expression was reported previously with 10-to 12-day PHA-treated blasts (32) and T-cell clones (33). The experiments reported here thus deal with an analysis of T-cell response during the initial exposure to IL-2.…”

Section: Resultsmentioning

confidence: 89%

“…This differed markedly from the succeeding rounds of cell division, in which the entire cell cycle can be less than 20 h (11). Transcription of the c-myc gene was reported to be positively regulated by IL-2 binding when rapidly dividing cells from a murine T-cell clone (33) or cells derived by 10 to 12 days of PHA stimulation in vitro (32) were analyzed. In the experiments reported here, no positive effect of IL-2 binding on c-myc expression was observed.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of human T-lymphocyte gene expression by interleukin 2: immediate-response genes include the proto-oncogene c-myb.

Pauza¹

1987

Mol. Cell. Biol.

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Antigen-stimulated human T lymphocytes must bind the immunoregulatory hormone interleukin 2 (IL-2) if they are to transit from the Gl to the S phase of the cell cycle. Indirect methods, such as the measurement of thymidine uptake rates, were previously the only means available for exploring the mechanism of action of IL-2. Several cDNA clones have been isolated which are expressed subsequent to IL-2 binding, and the expression of two of these genes, Tact52 and Tact75, is regulated directly at the level of transcription; expression of the proto-oncogene c-myb is also regulated directly by IL-2 binding. These genes thus constitute a set which is coordinately regulated in the course of the transition from Gl to S phase of human T lymphocytes, and their expression depends on IL-2 binding.The molecular mechanisms regulating cellular proliferation increasingly appear to be dependent on the binding of growth factors to cells (14). The consequences of growth factor binding include rapid changes in the expression of a small number of genes (13,18), and the mechanisms regulating coordinate expression of these induced genes clearly are critical in the control of cellular proliferation. Particular attention has been paid to the role of proto-oncogene expression in response to growth factor stimulation (14, 18) because of the examples in which altered expression of these genes, or their homologs, has been correlated with unregulated cellular proliferation (2, 26).The control of human T lymphocyte proliferation provides a unique model system for the analysis of growth regulation by extracellular factors. Quiescent T cells can be activated by antigenic or mitogenic stimulation and, in the presence of appropriate growth factors, will then proliferate in vitro or in vivo (4, 35). The entity of critical importance in this system is the glycopeptide hormone interleukin-2 (IL-2), which is required by stimulated T cells to effect transit from the Gl to S phase of the cell cycle (4, 20). The IL-2 requirement is absolute in the initial and in all subsequent rounds of T-cell division (4, 11, 23).Our previous work (submitted for publication) represents the initial work on the isolation of genes whose expression is regulated directly by IL-2 binding. Two of those genes, Tact52 and Tact75, are now shown to be directly responsive to IL-2 binding; indeed, the growth factor induces both transcription and mRNA accumulation from these genes. To these two genes is now added the proto-oncogene c-myb, which is also regulated at the transcriptional level. This stands in contrast to the recent report that c-myb transcription is not regulated in avian thymocytes, even though cell cycle-dependent changes in c-myb expression in both the avian transformed T-lymphoid line MSB-1 and chicken embryo fibroblasts were observed (39).The present findings attest that the mechanism of IL-2 control of T-cell entry into the S phase involves the trancriptional regulation of a small number of genes. We again focus attention on the regulation of a proto-oncogene as a...

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Regulation of human T-lymphocyte gene expression by interleukin 2: immediate-response genes include the proto-oncogene c-myb.

Pauza¹

1987

Mol. Cell. Biol.

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“…Whereas DP thymocytes express cell cycle proteins and exist in a quasiactivated state (32), splenic T cells are mostly quiescent. Only upon antigen encounter do splenic T cells increase glycolysis, nutrient uptake, proliferation, and c-Myc expression (33)(34)(35). We reasoned that mitogen-induced, endogenous Myc expression in splenic T cells would trigger apoptosis in MntTcKO T cells, similar to the enhanced apoptosis of unstimulated MntTcKO+TMyc T cells (Fig.…”

Section: Overexpression Of Myc Increases Dependence On Mnt-mediatedmentioning

confidence: 99%

A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis

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Ota

Zhou

et al. 2012

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

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Mnt (Max's next tango) is a Max-interacting transcriptional repressor that can antagonize both the proproliferative and proapoptotic functions of Myc in vitro. To ascertain the physiologically relevant functions of Mnt and to help define the relationship between Mnt and Myc in vivo, we generated a series of mouse strains in which Mnt was deleted in T cells in the absence of endogenous c-Myc or in the presence of ectopic c-Myc. We found that apoptosis caused by loss of Mnt did not require Myc but that ectopic Myc expression dramatically decreased the survival of both Mnt-deficient T cells in vivo and Mnt-deficient MEFs in vitro. Consequently, Myc-driven proliferative expansion of T cells in vitro and thymoma formation in vivo were prevented by the absence of Mnt. Consistent with T-cell models, mouse embryo fibroblasts (MEFs) lacking Mnt were refractory to oncogenic transformation by Myc. Tumor suppression caused by loss of Mnt was linked to increased apoptosis mediated by reactive oxygen species (ROS). Thus, although theoretically and experimentally a Myc antagonist, the dominant physiological role of Mnt appears to be suppression of apoptosis. Our results redefine the physiological relationship between Mnt and Myc and requirements for Myc-driven oncogenesis.cancer | antioxidant | buthionine sulfoximine | Ras | Bcl-2

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“…The down-regulation of c-fos mRNA Ievels in 3T3, HL-60 and U937 cells was observed to be caused by transcriptional shutoff and a rapid degradation of the c-fos mRNA [10,11]. In normal mause lymphocytes, c-myc expression is stimulated by various mitogens and growth factors [1,12,13]; however, the Ievels of cmyc mRNA in mouse T lymphocytes depend on the type of mitogen used and the subpopulation of T cells investigated [14]. The down-regulation of c-myc mRNA Ievels in lymphocytes and various cell lines is caused by post-transcriptional mechanisms influencing the stability of mRNA and treatment of cells with cycloheximide (CHI) le.ads to accumulation of cmyc mRNA [1, 2, '15-18].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of cellular oncogene expression in mouse lymphocytes II. Regulation of c‐fos and c‐myc gene expression

Schneider‐Schaulies¹,

Schimpl²,

Wecker³

1987

Eur J Immunol

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Newly isolated lymphocytes from mouse spleens express the c‐fos oncogene even in the absence of mitogen with maximal mRNA levels 60 min post preparation of single cell suspension, whereas c‐myc mRNA levels increase only after mitogenic stimulation with maximal mRNA levels 6 h post stimulation. The half‐lives of c‐fos mRNA are generally very short; they increase from 14 min (after 30 min of culture) to 70 min (after 2 h of culture). The half‐lives of c‐myc mRNA decrease from 50 min (at 2 and 6 h post stimulation with concanavalin A) to 12 min (at 48 h post stimulation). The c‐fos gene transcription is already turned on in time‐0 lymphocytes 10 min after disruption of the organ structure of the spleens and is down‐regulated after 2 h and later. In nuclear run‐on experiments with nonstimulated lymphocytes there is already significant transcription of the first exon of c‐myc, but almost no elongation of the transcript to exon 2 and 3. In concanavalin A‐treated lymphocytes elongation is stimulated about 5‐fold within 6 h and returns to background levels at 48 h post stimulation. The nuclear run‐on analyses of nonactivated lymphocytes showed a signal for RNA complementary to c‐myc mRNA detected with a probe specific for the exon 1/intron 1 boundary of c‐myc, which disappeared with increasing time of concanavalin A stimulation. This anti‐sense transcription may play a role in regulating the elongation of c‐myc transcripts.

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Recombinant interleukin 2 regulates levels of c-myc mRNA in a cloned murine T lymphocyte.

Cited by 71 publications

References 48 publications

Regulation of human T-lymphocyte gene expression by interleukin 2: immediate-response genes include the proto-oncogene c-myb.

Regulation of human T-lymphocyte gene expression by interleukin 2: immediate-response genes include the proto-oncogene c-myb.

A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis

Kinetics of cellular oncogene expression in mouse lymphocytes II. Regulation of c‐fos and c‐myc gene expression

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