Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells.

Bryan, R.J.; Li, Yongqin; Lai, Jenn‐Haung; Van, Mai; Rice, Nancy R.; Rich, Robert R.; Tan, Tse‐Hua

doi:10.1128/mcb.14.12.7933

Cited by 79 publications

(74 citation statements)

References 60 publications

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“…The activation of protein kinase C and IB kinase takes place within minutes after engagement of TCR, and nuclear translocation of RelA is observed within 15 min after stimulation. In contrast, nuclear translocation of c-Rel takes place 3-4 h after stimulation and also requires de novo synthesis of protein (6,17,18). This suggests that TCR-induced c-Rel nuclear translocation requires a signaling pathway distinct from the one that activates RelA.…”

Section: To Induce Sustained Activation Of Erk T Cells Required Contmentioning

confidence: 76%

A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation

Koike

Yamagishi

Hatanaka

et al. 2003

Journal of Biological Chemistry

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Engagement of the T cell antigen receptor (TCR) rapidly induces multiple signal transduction pathways, including ERK activation. Here, we report a critical role for ERK at a late stage of T cell activation. Inhibition of the ERK pathway 2-6 h after the start of TCR stimulation significantly impaired interleukin-2 (IL-2) production, whereas the same treatment during the first 2 h had no effect. ERK inhibition significantly impaired nuclear translocation of c-Rel with a minimum reduction of NF-AT activity. Requirement for sustained ERK activation was also confirmed using primary T cells. To induce sustained activation of ERK, T cells required continuous engagement of TCR. Stimulation of T cells with soluble anti-TCR antibody resulted in activation of ERK lasting for 60 min, but failed to induce IL-2 production. In contrast, plate-bound anti-TCR antibody activated ERK over 4 h and induced IL-2. Furthermore, T cells treated with soluble anti-TCR antibody produced IL-2 when phorbol 12-myristate 13-acetate, which activates ERK, was present in the culture medium 2-6 h after the start of stimulation. Together, the data demonstrate the presence of a novel activation process following TCR stimulation that requires ERK-dependent regulation of c-Rel, a member of the NF-B family.

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Section: To Induce Sustained Activation Of Erk T Cells Required Contmentioning

confidence: 76%

A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation

Koike

Yamagishi

Hatanaka

et al. 2003

Journal of Biological Chemistry

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“…IKK and TBK1 are structurally similar to the classical IKK␣␤ kinases, with an N-terminal kinase domain and Cterminal leucine zipper-like and helix-loop-helix domains but share only 27% primary sequence identity with IKK␣, whereas IKK and TBK1 possess 61% sequence identity to each other and are enzymatically similar (15). In contrast to the role of the IKK␣␤␥ complex in the phosphorylation of I B␣ at Ser 32 and Ser 36 , TBK1 and IKK phosphorylate I B␣ solely on Ser 36 (11) and the physiological significance of this phosphorylation in NF-B activation remains unclear. However, a distinct role for IKK and TBK1 in NF-B activation was suggested by the observation that a kinase inactive, dominant negative form of IKK , IKK (K38A), blocked NF-B induction in response to PMA or TCR stimulation, but not in response to TNF-␣ or IL-1 cytokines (11).…”

mentioning

confidence: 96%

“…In unstimulated cells, complex containing cRel and I B␣ shuttle from the cytoplasm to the nucleus, with a balance in favor of the cytoplasm. In the cytoplasm, IKK phosphorylates (P) cRel and I B␣ on Ser 36 , resulting in the dissociation of the I B␣/cRel containing dimers. The freed cRel accumulates in the nucleus, where it undergoes additional regulation for full transcriptional activity.…”

Section: Figurementioning

confidence: 99%

Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε

Harris

Oliere

Sharma

et al. 2006

The Journal of Immunology

102

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The NF-κB transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-κB activity is mainly regulated through the phosphorylation of IκB by the IκB kinase (IKK) complex IKKαβγ, leading to proteasome-mediated degradation of IκB, nuclear translocation of NF-κB dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-κB p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-κB activator (TANK)-binding kinase (TBK)1 and IKKε, are also thought to play a role in NF-κB regulation, but their functions remain unclear. TBK1 and IKKε were recently described as essential regulators of IFN gene activation through direct phosphorylation of the IFN regulatory factor-3 and -7 transcription factors. In the present study, we sought to determine whether IKKε and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKKε directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IκB/IKK pathway. IκBα degradation is not affected, but rather IKKε-mediated phosphorylation of cRel leads to dissociation of the IκBα-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKKε/TBK1 phosphorylation.

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“…Conversely, no significant increase in the nuclear levels of RelB and c-Rel was detected. c-Rel transcription factor has been known to bind to and activate the CD28 response element (RE) within the IL-2 promoter, and CD28 costimulation accelerates the kinetics of c-Rel nuclear translocation (29). Thus, the total absence of c-Rel in the nucleus of CD28-stimulated T cells indicates that CD28, when engaged by B7 independently of TCR, can activate a distinct pool of NF-B subunits, potentially involved in the regulation of a different subset of genes.…”

Section: Cd28 Engagement By B7 Induces the Transcription Of Nf-b-regumentioning

confidence: 99%

CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits onIL-8andBcl-xLgene promoters

Marinari

Costanzo

Marzano

et al. 2004

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

108

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CD28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. The CD28 receptor can enhance T cell antigen receptor (TCR) signals, as well as deliver independent signals. Indeed, CD28 engagement by B7 can generate TCR-independent signals leading to I B kinase and NF-B activation. Here we demonstrate that the TCR-independent CD28 signal leads to the selective transcription of survival (Bcl-xL) and inflammatory (IL-8 and B cell activation factor, but not proliferative (IL-2), genes, in a NF-Bdependent manner. CD28-stimulated T cells actively secrete IL-8, and Bcl-xL up-regulation protects T cells from radiation-induced apoptosis. The transcription of CD28-induced genes is mediated by the specific recruitment of RelA and p52 NF-B subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-B sites on the IL-2 gene promoter after anti-CD3 stimulation, are not involved. Thus, we identify CD28 as a key regulator of genes important for both survival and inflammation. C D28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. Early studies on CD28 demonstrated that it provides a potent signal for the upregulation of several cytokines, acting at the level of both transcription and message stability. More recent studies have evidenced that CD28 plays a key role in enhancing T cell activation by the T cell antigen receptor (TCR) (1). As an integral component of the immunological synapse, CD28 plays a critical role in the recruitment of signaling molecules to the TCR (2). In particular, it has been recently demonstrated that CD28 enhances close contact between T cells and antigen-presenting cells and facilitates TCR signal transduction by amplifying phospholipase C␥1 activation and Ca 2ϩ response (3). The consequence of this action is an augmentation of early TCR-mediated signal (4). Recent evidence showing that CD28 can mediate adhesion signals beyond costimulatory ones (3) has led to new interest and induced a new wave of investigation of the intriguing problems concerning the molecular mechanisms as well as the targets of CD28 as an independent signaling unit. CD28 stimulation can induce cytoskeletal rearrangements in T cells (5) or up-regulate IL-2-4 only when Vav and the adapter SLP-76 are overexpressed (6). However, the mediators and the molecular mechanisms, which govern the process whereby CD28 may deliver an autonomous signal, remain unknown. We have recently demonstrated that CD28 engagement by B7 can generate TCRindependent signals leading to I B kinase (IKK) and NF-B activation (7) and that Vav-1 acts as the upstream regulator of this signaling pathway (8).NF-B͞Rel transcription factors are critical regulators of the positioning of immune responses to integrate information from both innate and adaptive immune signaling pathways. In mammals, this family consists of five members that form homo-and heterodimeric complexes including NF-B1 (p50 and its precursor p105), NF-B2 (p52 and its precursor p100), RelA...

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Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells.

Cited by 79 publications

References 60 publications

A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation

A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation

Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε

CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits onIL-8andBcl-xLgene promoters

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