Interleukin 2 activates STAT5 transcription factor (mammary gland factor) and specific gene expression in T lymphocytes.

Gilmour, Kimberly; Pine, Richard; Reich, Nancy C.

doi:10.1073/pnas.92.23.10772

Cited by 69 publications

(46 citation statements)

References 41 publications

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“…35). In contrast, treatment of splenocytes from both wild-type and IL-1212R␤2-deficient mice with IL-2 resulted in phosphorylation of STAT-5 as expected (36,37). Taken together, the control of IL-12R␤2 expression may constitute an important mechanism for regulating IL-12 responsiveness.…”

Section: Discussionmentioning

confidence: 81%

IL-12 Receptor β2 (IL-12Rβ2)-Deficient Mice Are Defective in IL-12-Mediated Signaling Despite the Presence of High Affinity IL-12 Binding Sites

Wang

Gadina

et al. 2000

The Journal of Immunology

142

121

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Two subunits of the IL-12 receptor (IL-12R), IL-12Rβ1 and IL-12Rβ2, have been identified and cloned. Previous studies demonstrated that the IL-12Rβ1 subunit was required for mouse T and NK cells to respond to IL-12 in vivo. To investigate the role of IL-12Rβ2 in IL-12 signaling, we have generated IL-12Rβ2-deficient (IL-12Rβ2−/−) mice by targeted mutation in embryonic stem (ES) cells. Although Con A-activated splenocytes from IL-12Rβ2−/− mice still bind IL-12 with both high and low affinity, no IL-12-induced biological functions can be detected. Con A-activated splenocytes of IL-12Rβ2−/− mice failed to produce IFN-γ or proliferate in response to IL-12 stimulation. NK lytic activity of IL-12Rβ2−/− splenocytes was not induced when incubated with IL-12. IL-12Rβ2−/− splenocytes were deficient in IFN-γ secretion when stimulated with either Con A or anti-CD3 mAb in vitro. Furthermore, IL-12Rβ2−/− mice were deficient in vivo in their ability to produce IFN-γ following endotoxin administration and to generate a type 1 cytokine response. IL-12-mediated signal transduction was also defective as measured by phosphorylation of STAT4. These results demonstrate that although mouse IL-12Rβ1 is the subunit primarily responsible for binding IL-12, IL-12Rβ2 plays an essential role in mediating the biological functions of IL-12 in mice.

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Section: Discussionmentioning

confidence: 81%

IL-12 Receptor β2 (IL-12Rβ2)-Deficient Mice Are Defective in IL-12-Mediated Signaling Despite the Presence of High Affinity IL-12 Binding Sites

Wang

Gadina

et al. 2000

The Journal of Immunology

142

121

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“…Results represent averages of three separate transfection experiments. and adrenal gland (1,17,46,48,52,56), one could envision Stat involvement in SAA gene expression by forming a proteinprotein complex with SAF. Such a possibility is remote, however, in light of the finding that anti-Stat antibodies have no effect on SAF binding to SAS (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel cis-Acting Element Is Essential for Cytokine-Mediated Transcriptional Induction of the Serum Amyloid A Gene in Nonhepatic Cells

Ray

1996

Molecular and Cellular Biology

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Serum amyloid A (SAA) is a plasma protein which has been associated with several diseases, including amyloidosis, arthritis, and atherosclerosis, and its abnormal expression, particularly in nonhepatic cells, is implicated in the pathogenesis of these diseases. Transfection and DNA-binding studies were performed to investigate the mechanism controlling cytokine-induced, nonhepatic expression of the SAA gene. We have identified a novel promoter, located between positions ؊280 and ؊224, that confers interleukin-6 (IL-6) inducibility to an SAA-chloramphenicol acetyltransferase reporter gene in both nonhepatic and hepatic cells. DNase I protection assays revealed, within this region, three homologous highly pyrimidine rich octanucleotide sequence motifs, termed SAA-activating sequences (SAS). Specific mutations within these three SAS motifs severely reduced IL-6-mediated induction of the reporter gene in transfected nonhepatic cells but not in liver cells. A nuclear factor activated by IL-6 in both hepatic and nonhepatic cells efficiently interacts with the SAS. The induction kinetics and cycloheximide sensitivity of this SAS-binding factor (SAF) suggested that de novo synthesis of this factor itself or an activator protein is essential. Loss of DNA-binding ability as a result of in vitro dephosphorylation, induction of SAA-chloramphenicol acetyltransferase reporter gene activity in the presence of a protein phosphatase inhibitor, and loss of IL-6-mediated inducible DNA-binding activity and reporter gene activation in the presence of genistein, a protein kinase inhibitor, further indicate that a phosphorylation step is necessary for the activation of SAF. Our results suggest that SAF is a key regulator of cytokine-mediated SAA gene expression in some nonhepatic cells.

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“…In particular, Stat5, for which two isoforms Stat5a and Stat5b differing in their C-terminal tail were characterized in mouse mammary gland (28), has been shown to be vital for hormonal induction of ␤-casein gene transcription in mammary gland of lactating animals (29) and in heterologous cell systems (30). Stat5 activation has also recently been shown to correlate with mitogenic signaling in response to PRL (31). Therefore, Stat5 appears to be a key player in PRL-induced gene activation and cell proliferation.…”

Section: Prolactin (Prl)mentioning

confidence: 99%

Prolactin Receptor Regulates Stat5 Tyrosine Phosphorylation and Nuclear Translocation by Two Separate Pathways

Ali¹,

Ali

1998

Journal of Biological Chemistry

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The SH2 domain containing signal transducers and activators of transcription (Stat proteins) are effector molecules downstream of cytokine receptors. Ligand/ receptor engagement triggers Stat proteins tyrosine phosphorylation, dimerization, and translocation to the nucleus where they regulate gene transcription. Stat5, originally identified as a mammary gland growth factor, is an essential mediator of prolactin (PRL)-induced milk protein gene activation. Prolactin receptor (PRLR) is a member of the cytokine/growth hormone/PRL receptor superfamily. The mechanism through which PRLR modulates Stat5 tyrosine phosphorylation, nuclear translocation, and DNA binding was analyzed in HC11 cells, a mammary epithelial cell line, and 293-LA cells, a human kidney cell line stably overexpressing Jak2 kinase. We have found that in HC11 cells, Stat5 is specifically activated by PRL treatment, demonstrating that Stat5 is a physiological substrate downstream of PRLR. Furthermore, using different forms natural forms of the PRLR as well as receptor tyrosine to phenylalanine mutant forms, we determined that tyrosine phosphorylation of Stat5 is independent of PRLR phosphotyrosines. We established, however, that the C-terminal tyrosine of the PRLR Nb2 form, Tyr 382 , plays an essential positive role in PRLR-dependent Stat5 nuclear translocation and subsequently DNA binding. All together, our data propose a new model for activation of Stat5 through the PRLR, suggesting that Stat5 tyrosine phosphorylation and nuclear translocation are two separately regulated events. Prolactin (PRL)1 is a pituitary polypeptide hormone as well as a local growth factor that regulates several physiological functions such as reproduction, promotion of the growth and differentiation of the mammary gland, and immune function (1). PRL interacts with specific cell surface receptors expressed on different target tissues (reviewed in Ref. 2).The receptor for PRL (PRLR) belongs to a large group of receptors known as the cytokine/GH/PRL receptor superfamily, which includes the receptors for GH, EPO, granulocyte-macrophage colony-stimulating factor, and several interleukins (2, 3). These receptors share common extracellular structural motifs such as two disulfide loops and intracellular such as the proline-rich Box1 homology domain. These receptors do not possess intrinsic kinase activity but signal through cytoplasmic protein tyrosine kinases of the Janus kinase family (Jak/Tyk kinases) and the Src-kinase family. Ligand binding to the cytokine/GH/PRL receptor family induces receptor dimerization and activation of the associated kinases. This leads in turn to tyrosine phosphorylation of multiple cellular proteins including the receptors themselves (4).The downstream signaling molecules activated by this receptor family have not been completely elucidated. However, it has been shown that several of the SH2 domain containing molecules interact with cytokine receptors, e.g. phospholipid metabolizing enzymes, phospholipase C-␥, and the regulatory unit of phosphatidylino...

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Interleukin 2 activates STAT5 transcription factor (mammary gland factor) and specific gene expression in T lymphocytes.

Cited by 69 publications

References 41 publications

IL-12 Receptor β2 (IL-12Rβ2)-Deficient Mice Are Defective in IL-12-Mediated Signaling Despite the Presence of High Affinity IL-12 Binding Sites

IL-12 Receptor β2 (IL-12Rβ2)-Deficient Mice Are Defective in IL-12-Mediated Signaling Despite the Presence of High Affinity IL-12 Binding Sites

A Novel cis-Acting Element Is Essential for Cytokine-Mediated Transcriptional Induction of the Serum Amyloid A Gene in Nonhepatic Cells

Prolactin Receptor Regulates Stat5 Tyrosine Phosphorylation and Nuclear Translocation by Two Separate Pathways

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