The C-terminal region of human NFATc2 binds cJun to synergistically activate interleukin-2 transcription

Nguyen, Tuan; Kim, Loree J.; Walters, Ryan D.; Drullinger, Linda F.; Lively, Tricia N.; Kugel, Jennifer F.; Goodrich, James A.

doi:10.1016/j.molimm.2010.05.287

Cited by 20 publications

(27 citation statements)

References 41 publications

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“…Such separable binding of NFAT family members has also been observed in human Jurkat cells stimulated with PMA and ionomycin (39). Only NFAT1 has a unique C-terminal domain, which is reported to function as a transactivation domain as well as an interaction domain with Jun (39, 40). This domain may contribute to the initial change at the Il2 promoter.…”

Section: Discussionmentioning

confidence: 73%

Two-Step Binding of Transcription Factors Causes Sequential Chromatin Structural Changes at the Activated IL-2 Promoter

Ishihara

Schwartz

2011

The Journal of Immunology

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Most gene promoters have multiple binding sequences for many transcription factors, but the contribution of each of these factors to chromatin remodeling is still unclear. Although we previously found a dynamic change in the arrangement of nucleosome arrays at the Il2 promoter during T cell activation, its timing preceded that of a decrease in nucleosome occupancy at the promoter. Here we show that the initial nucleosome rearrangement was temporally correlated with the binding of NFAT1 and AP-1 (Fos/Jun), while the second step occurred in parallel with the recruitment of other transcription factors and RNA polymerase II. Pharmacologic inhibitors for activation of NFAT1 or induction of Fos blocked the initial phase in the sequential changes. This step was not affected, however, by inhibition of c-Jun phosphorylation, which instead blocked the binding of the late transcription factors, the recruitment of CREB-binding protein (CBP) and the acetylation of histone H3 at lysine 27 (H3K27ac). Thus, the sequential recruitment of transcription factors appears to facilitate two separate steps in chromatin remodeling at the Il2 locus.

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Section: Discussionmentioning

confidence: 73%

Two-Step Binding of Transcription Factors Causes Sequential Chromatin Structural Changes at the Activated IL-2 Promoter

Ishihara

Schwartz

2011

The Journal of Immunology

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“…Other combinations of NFATc1, NFATc2, cJun, and cFos were unable to achieve high levels of synergistic activation. Moreover, we found that the C-terminal activation domain of NFATc2 (amino acids 688-921) is capable of directly binding cJun homodimers, but not cJun/cFos heterodimers (Nguyen et al, 2010). This C-terminal region of NFATc2 is required for IL-2 transcriptional synergy between NFATc2 and cJun in Jurkat cells.…”

Section: Introductionmentioning

confidence: 96%

“…There are five members of the NFAT family, with NFATc1 and NFATc2 being the primary members expressed in T cells (Lyakh et al, 1997). Upon T cell activation NFATc2 rapidly enters the nucleus and occupies the promoter region of the IL-2 gene, whereas NFATc1 is synthesized upon T cell stimulation, enters the nucleus, and binds the IL-2 promoter several hours later (Loh et al, 1996; Lyakh et al, 1997; Nguyen et al, 2010; Timmerman et al, 1996). NFATc1 and NFATc2 share similar overall structural motifs with the distinguishing feature being the presence of a C-terminal activation domain on NFATc2 (amino acids 688-921) that is absent from NFATc1 (Hogan et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…NFATc1 or NFATc2 bind cooperatively to DNA with dimers of the AP-1 family, comprised of Jun and Fos proteins (Chinenov and Kerppola, 2001; Ransone et al, 1989; Turner and Tjian, 1989). Specifically, cJun –which can homo- and heterodimerize – and cFos – which can only heterodimerize – function in IL-2 transcriptional activation (Ishihara and Schwartz, 2011; Nguyen et al, 2010). The IL-2 promoter spans from approximately −300 to +40 relative to the transcription start site (TSS) (Rooney et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…We previously tested the response of the IL-2 promoter to different combinations of overexpressed NFAT and AP-1 proteins in Jurkat cells (Nguyen et al, 2010). The combination of NFATc2 and cJun was uniquely able to achieve high levels of transcriptional synergy, defined by the level of expression in the presence of both proteins being greater than the sum of the levels observed with either protein alone.…”

Section: Introductionmentioning

confidence: 99%

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NFATc2 recruits cJun homodimers to an NFAT site to synergistically activate interleukin-2 transcription

Walters¹,

Drullinger²,

Kugel³

et al. 2013

Molecular Immunology

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Transcription of interleukin-2 (IL-2), a pivotal cytokine in the mammalian immune response, is induced by NFAT and AP-1 transcriptional activators in stimulated T cells. NFATc2 and cJun drive high levels of synergistic human IL-2 transcription, which requires a unique interaction between the C-terminal activation domain of NFATc2 and cJun homodimers. Here we studied the mechanism by which this interaction contributes to synergistic activation of IL-2 transcription. We found that NFATc2 can recruit cJun homodimers to the −45 NFAT element, which lacks a neighboring AP-1 site. The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 in the absence of DNA and this interaction is inhibited by AP-1 DNA. When the −45 NFAT site was replaced by either a NFAT/AP-1 composite site or a single AP-1 site the specificity for cJun homodimers in synergistically activating IL-2 transcription was lost, and cJun/cFos heterodimers strongly activated transcription. These studies support a model in which IL-2 transcriptional synergy is mediated by the unique recruitment of a cJun homodimer to the −45 NFAT site by NFATc2, where it acts as a co-activator for IL-2 transcription.

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Myc and AP-1 expression in T cells and T-cell activation in patients after hematopoietic stem cell transplantation

et al. 2014

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Regeneration of the immune system after hematopoietic stem cell transplantation (HSCT) is a slow process. We attempted to identify problems in the recovery of the immune system by examining expressions of early event cell cycle proteins Myc, Jun, and Fos, as well as DNA binding of Myc, activating protein 1 (AP-1), and CD4 cell activation values, in phytohemagglutinin-activated T lymphocytes taken from patients after HSCT. HSCT patients showed lower protein expression levels of Myc and Jun, as well as Myc and AP-1 DNA-binding levels, as compared to healthy controls. C-Jun was lower in long-term survivors of HSCT than short-term survivors. Adenosine triphosphate (ATP) values in CD4 cells were also lower in HSCT patients than healthy controls, but showed a time-dependent increase post-transplant. Non-surviving patients showed lower levels of both Fos protein and ATP as compared to surviving patients and a negative correlation between Fos values and lymphocyte percentage that was not present in surviving patients. There was a strong positive correlation between Fos values and lymphocyte percentage and between AP-1 values and white blood count, in patients without graft-versus-host disease (GVHD), that did not exist in patients who suffered from GVHD. Patients 2 years post-HSCT showed a positive correlation between AP-1 and Myc DNA-binding protein values, similar to those values found in healthy controls. Our study identified significant factors that account for the delay in immune reconstitution after transplant; this knowledge may improve the management of post-HSCT patients.

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The C-terminal region of human NFATc2 binds cJun to synergistically activate interleukin-2 transcription

Cited by 20 publications

References 41 publications

Two-Step Binding of Transcription Factors Causes Sequential Chromatin Structural Changes at the Activated IL-2 Promoter

Two-Step Binding of Transcription Factors Causes Sequential Chromatin Structural Changes at the Activated IL-2 Promoter

NFATc2 recruits cJun homodimers to an NFAT site to synergistically activate interleukin-2 transcription

Myc and AP-1 expression in T cells and T-cell activation in patients after hematopoietic stem cell transplantation

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