Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of NF-kappa B suggest that this enhancer binding activity corresponds to a family of at least four proteins (p50, p55, p75, and p85) differentially induced with biphasic kinetics during T cell activation. While p55 and p50 are closely related to the 50 kd DNA binding subunit of NF-kappa B, p75 and p85 exhibit DNA binding properties that distinguish them from this 50 kd polypeptide and its regulatory subunits I kappa B and p65. All four members of this kappa B-specific protein family are structurally related to the v-Rel oncoprotein and one, p85, appears identical to human c-Rel. v-Rel, but not nontransforming v-Rel mutants, binds to the kappa B enhancer and inhibits NF-kappa B-activated transcription from the IL-2 receptor alpha promoter and HIV-1 LTR. These findings suggest a Rel-related family of kappa B enhancer binding proteins and raise the possibility that the transforming activity of v-Rel is linked to its inhibitory action on cellular genes under NF-kappa B control.
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PMID:The v-rel oncogene encodes a kappa B enhancer binding protein that inhibits NF-kappa B function. 222 78

Stimulation of primary human T-lymphocytes via CD2 and CD28 adhesion molecules induces a long-lasting proliferation (> 3 weeks). This potent activation does not require accessory cells, such as monocytes, but depends on persistent interleukin 2 (IL-2) secretion and receptivity, which is associated with high and prolonged expression of the inducible CD25/IL-2 receptor alpha (IL-2R alpha) chain gene. The transcription factor NF-kappa B participates in the regulation of both IL-2 and IL-2R alpha genes, as well as multiple cellular genes involved in T-cell proliferation. To evaluate the role of NF-kappa B in human peripheral blood T-lymphocytes, we previously analyzed the activation of NF-kappa B-related complexes in response to CD2+CD28 costimulation. We demonstrated a long-term induction of p50/p65 heterodimer, a putative p65/c-Rel heterodimer, and a constitutive nuclear expression of KBF1/p50 homodimers. As the role of p50 remains unclear, we focused our present study on NF-kappa B1 (p50/p105) gene regulation. Using electrophoretic mobility shift assays and Western and Northern blot analyses, we studied NF-kappa B1 gene expression during T-cell stimulation via CD2+CD28. We observed a transient 4- to 5-fold increase of NF-kappa B1 gene expression at both the mRNA and protein levels, lasting for at least 24 h. p50 DNA-binding activity apparently stays highly controlled when p105 expression is enhanced by a physiological stimulus of peripheral blood T-cells. Partial inhibition of p50 and p105 expression by NF-kappa B1 antisense oligonucleotides significantly reduced T-cell proliferation and CD25/IL-2R alpha cell surface expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of NF-kappa B1 (p50/p105) gene expression in activation of human blood T-lymphocytes via CD2 and CD28 adhesion molecules. 790 83

The cascade of events within the first few minutes of T cell stimulation has been well characterized. Although many second messengers have been shown to be necessary and sufficient for T cell activation in a number of model systems, the rate-limiting step in peripheral T cells has not been demonstrated. To model effective versus ineffective CD3-mediated stimulation in peripheral T cells, we used two anti-CD3 mAbs that differ in their ability to stimulate purified T cells: OKT3, which causes early second messenger generation but is unable to activate T cells without a second signal, and 64.1, which stimulates T cell proliferation on its own. We found that tyrosine kinase activity was similar for both mAbs over a period of hours. However, the inositol phosphate response was stronger for 64.1 than for OKT3. To tie these events to gene activation, we measured NF-kappa B and NF-AT activity in the nucleus after anti-CD3 stimulation. Both stimuli induced the appearance of the NF-kappa B components (c-Rel, p65 (RelA), and p50 (NF-kappa B1)) and NF-kappa B DNA binding activity in the nucleus. However, only 64.1 induced NF-AT in the nucleus, correlating with its ability to activate T cells. Thus, NF-AT induction and IL-2 secretion were correlated with the levels of inositol phosphate release but not with gross levels of tyrosine kinase activity induced late following the response. On the other hand, NF-kappa B induction and IL-2 receptor expression occurred even with the smaller second messenger response generated by OKT3.
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PMID:Long-term inositol phosphate release, but not tyrosine kinase activity, correlates with IL-2 secretion and NF-AT induction in anti-CD3-activated peripheral human T lymphocytes. 803 43

Stimulation of highly purified human T-cells via CD2 and CD28 adhesion molecules induces and maintains proliferation for more than 3 weeks. This potent interleukin 2 (IL-2)-dependent activation does not require monocytes or accessory cells. Long-lasting IL-2 receptivity is associated with high-level expression of the inducible IL-2 receptor alpha chain (IL-2R alpha) gene that is regulated at both transcriptional and posttranscriptional levels. Increase of IL-2R alpha gene transcription involves the enhanced binding of the transcription factor NF-kappa B to its consensus sequence in the 5'-regulatory region of the IL-2R alpha gene. To dissect the molecular basis for the unusually persistent transcription of the IL-2R alpha gene, we analyzed nuclear NF-kappa B binding to a radiolabeled IL-2R alpha kappa B-specific oligonucleotide probe during the time course of CD2 + CD28 activation. Resting T-cell nuclear extracts contained KBF1/p50 homodimer. After stimulation, two new kappa B-specific complexes were identified as NF-kappa B p50-p65 heterodimer and putative c-Rel homodimer or c-Rel-p65 heterodimer. Both inducible complexes persisted for at least 3 weeks. Their relative levels were very similar for the duration of proliferation. In parallel, CD2 + CD28 activation triggered a significant intracellular thiol decrease, suggesting that oxygen radicals are involved in the signaling pathway of adhesion molecules. Finally, micromolar amounts of pyrrolidine dithiocarbamate, an oxygen radical scavenger that efficiently blocked the nuclear appearance of NF-kappa B in T-lymphocytes, also inhibited IL-2 secretion, IL-2R alpha cell surface expression, and T-cell proliferation. Together, these results suggest that NF-kappa B plays an important role in long-term activation of human primary T-lymphocytes via CD2 + CD28.
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PMID:Activation of primary human T-lymphocytes through CD2 plus CD28 adhesion molecules induces long-term nuclear expression of NF-kappa B. 809 18

Members of the NF-kappa B/Rel family of transcription factors are involved in the transcriptional regulation of numerous polypeptides important to the immune response and cellular growth. Several genes regulated in part by NF-kappa B/Rel such as interleukin 2, IL-2 receptor alpha, and GM-CSF are trans-activated via an indirect association with the HTLV-I Tax protein in virus-infected and transformed T cells. In this study, we have investigated the interactions between Tax and NF-kappa B/Rel in an attempt to elucidate the mechanism of Tax mediated trans-activation and its role in leukemogenesis. Transfection studies were performed in Jurkat T cells using expression vectors for individual NF-kappa B subunits and the Tax protein as well as an NF-kappa B regulated reporter plasmid. NF-kappa B proteins differentially trans-activated the HIV-1 enhancer-CAT reporter; co-expression of Tax abrogated the inhibitory effect of I kappa B alpha and a trans-dominant negative mutant of p65 (p65 delta), indicating that Tax was a trans-dominant activator of NF-kappa B-regulated genes. Co-immunoprecipitation studies with extracts from transfected cells and NF-kappa B and Tax subunit specific antibodies revealed that Tax did not co-immunoprecipitate with p50/p105, c-Rel, or I kappa B; however, antibody specific to p65 was able to co-immunoprecipitate a 40kDa protein from Tax-transfected cells. Previous studies have demonstrated a physical interaction between Tax protein and p100, indicating that Tax may preferentially associate with specific NF-kappa B proteins.
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PMID:Interactions between HTLV-I Tax and NF-kappa B/Rel proteins in T cells. 815 9

Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is known to have both negative and positive effects on the activation mechanisms of T lymphocytes. The authors have analysed the effect of increased cAMP on the activation of NF-kappa B transcription factor. This factor controls the expression of several genes (e.g. IL-2 and IL-2 receptor) involved in the activation and proliferation of T cells. The authors found that elevation of intracellular cAMP in Jurkat T leukaemia cells activated with phorbol ester (PDBu)/calcium ionophore (A23187) increased the DNA-binding of NF-kappa B as detected by the electrophoretic mobility shift assay (EMSA). Analysis of the subunit composition of the DNA-binding complex indicated that the amount of c-Rel was enhanced while RelA was decreased. Analysis of the effect of elevated cAMP on the degradation of I kappa B-alpha and I kappa B-beta did not reveal an essential change in degradation kinetics of these inhibitor proteins. The elevation of cAMP did not increase the synthesis of c-Rel, but it enhanced the nuclear localization of this protein. Transfection of Jurkat cells with a plasmid kB/TK10-CAT indicated that the increased DNA-binding of c-Rel containing complexes seen in EMSA was also functional. These data imply that the strong and long-lasting c-Rel nuclear localization and DNA-binding induced by protein kinase A is not due to increased c-Rel synthesis or enhanced degradation of the I kappa B inhibitors. Therefore, a direct phosphorylation of the c-Rel protein is the most plausible explanation for these observations. Taken together, these results suggest that cAMP is able to regulate the expression of NF-kappa B-dependent genes in T cells by modifying the composition and subunit activity of NF-kappa B.
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PMID:Activation of the protein kinase A increases the DNA-binding and transcriptional activity of c-Rel in T cells. 865 53

Stimulation of highly purified primary T lymphocytes through CD2 and CD28 adhesion molecules induces a long-term proliferation, dependent on persistent autocrine secretion of interleukin 2 (IL-2), high and prolonged expression of inducible CD25/IL-2 receptor alpha chain (IL-2Ralpha), and secretion of growth factors such as the granulocyte-macrophage colony-stimulating factor (GM-CSF). CD28 costimulation appears to activate cytokine gene expression through conserved kappaB-related CD28 response (CD28RE) or cytokine 1 (CK-1) elements in addition to canonical NF-kappaB-binding sites. In this report, we assess: 1) the evolution of the expression, over an 8-day time period, of the Rel/NF-kappaB family of proteins in costimulated versus TcR/CD3-stimulated primary T cells; 2) the impact of changes on the in vitro occupancy of GM-CSF kappaB and CK-1, as well as IL-2Ralpha kappaB sites; and 3) the differential regulation of newly synthesized p65 and c-Rel by IkappaB proteins. We show that CD2+CD28 stimulation specifically induces, at maximal T cell proliferation phase, sustained nuclear overexpression of NFKB2 p52 and c-Rel subunits which might rely on long-lasting processing of p100 precursor for p52 and increased neosynthesis of c-Rel. This up-regulation correlates with sustained occupancy of GM-CSF kappaB and CK-1 elements by both proteins. Conversely, these subunits do not appear to bind to the IL-2Ralpha kappaB site. Costimulation, but not TcR/CD3 stimulation, appears supported by sustained down-regulation of both IkappaBalpha and -beta regulators. Furthermore, contrary to p65, c-Rel appears to display little affinity for p105, p100 and IkappaBalpha regulators.
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PMID:Temporal and subunit-specific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation. 926 7

The binding of interleukin-2 (IL-2) to its receptor on normal T cells induces nuclear expression of nuclear factor kappaB (NF-kappaB), activation of the IL-2 receptor (IL-2R) alpha chain gene, and cell proliferation. In the present study, the role of IL-2R signaling in the growth of CD8+ T cell prolymphocytic leukemia (T-PLL) cells has been investigated. Flow cytometry revealed that primary leukemia cells from a patient with CD8+ T-PLL expressed IL-2Ralpha and beta chains, and the cells showed a proliferative response and an increase in IL-2Ralpha expression on culture with exogeneous IL-2. Northern blot analysis failed to detect IL-2 mRNA, suggesting that IL-2 may act in a paracrine manner in vivo. Electrophoretic mobility-shift assays revealed that recombinant IL-2 increased NF-kappaB binding activity in nuclear extracts of the leukemia cells, and Northern blot analysis showed that IL-2 increased the abundance of mRNAs encoding the NF-kappaB components c-Rel and KBF1 in these cells. IL-2 binding analysis demonstrated that IL-2 markedly increased the number of low affinity IL-2Rs on the leukemia cells, without an effect on the number of high-affinity IL-2Rs. These results show that IL-2 is capable of inducing the nuclear expression of NF-kappaB in primary CD8+ T-PLL cells, and that this effect is mediated, at least in part, at a pretranslational level.
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PMID:IL-2-induced growth of CD8+ T cell prolymphocytic leukemia cells mediated by NF-kappaB induction and IL-2 receptor alpha expression. 961 18

c-Rel is a lymphoid-specific member of the NF-kappaB/Rel family of transcriptional factors. To investigate the role of c-Rel in B lymphocyte function, we generated a c-Rel(-/-) mouse via a gene targeting approach. Although early lymphocyte development is normal in c-Rel(-/-) mice, there are significantly fewer B cells displaying a memory (IgM/IgD-) phenotype. Upon immunization, c-Rel(-/-) mice generate fewer B cells with a germinal center (PNAhi) phenotype. In vitro, c-Rel(-/-) B cells proliferate poorly upon ligation of their surface IgM or CD40 receptors or when stimulated with either lipopolysaccharide (LPS) or T cell help. Early molecular events that precede proliferation, such as increases in RNA synthesis as well as IL-2 receptor alpha chain expression, are greatly diminished in c-Rel(-/-) B cells. Furthermore, c-Rel(-/-) B cells are impaired in the ability to receive survival signals generated by anti-IgM or LPS. In contrast, CD40-mediated cell survival is normal in c-Rel(-/-) B cells, suggesting the involvement of a survival-signaling pathway that is independent of c-Rel. When c-Rel (-/-) B cells are co-stimulated with either anti-IgM and CD40 or LPS and CD40, they are rendered capable of progressing through the cell cycle. Finally, co-culture experiments suggest that the defects observed in c-Rel(-/-) B cells are intrinsic to the cell and can not be rescued through either cell-cell contact or addition of soluble factors. Thus, c-Rel is requisite for differentiation to the germinal center and memory B cells in vivo and is required for the transduction of survival and cell cycle progression signals mediated by anti-IgM and LPS in vitro. Furthermore, while c-Rel is involved in CD40-induced proliferation, it is apparently dispensable for the survival signals transduced by CD40.
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PMID:c-Rel is essential for B lymphocyte survival and cell cycle progression. 986 67

Regulatory T cell (Treg) development proceeds via a two-step process in which naive CD4(+) thymocytes are first converted into CD4(+)CD25(+)CD122(+)GITR(+)Foxp3(-) Treg progenitors, followed by a second step in which IL-2 converts these Treg progenitors into CD4(+)Foxp3(+) Tregs. The costimulatory molecule CD28 is required for efficient Treg development. However, the stage at which CD28 affects Treg development remains undefined. In this article, we demonstrate that Cd28(-/-) mice lack Treg progenitors. Furthermore, the P(187)YAP motif in the cytoplasmic tail of CD28, which links CD28 to Lck activation, is required for this process. In contrast, the Y(170)MNM motif, which links CD28 to PI3K activation, is not required for Treg progenitor development. Finally, the CD28/Lck pathway was shown to activate the NF-kappaB family of transcription factors. We demonstrate that c-Rel, but not NF-kappaB1, promotes the development of Treg progenitors. Thus, a CD28/c-Rel-dependent pathway is involved in initiating Treg development.
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PMID:Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. 2022 98


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