The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun

Jain, Jugnu; Pg, McCaffrey; Miner, Zoe; Tk, Kerppola; Jn, Lambert; Gl, Verdine; Curran, Tom; Av, Rao

doi:10.1038/365352a0

Cited by 728 publications

(536 citation statements)

References 28 publications

Supporting

Mentioning

514

Contrasting

Unclassified

Order By: Relevance

“…Moreover, we had shown that Tpl-2 activates NFAT, a complex transcription factor composed of NFAT and AP1 components, whose activation is obligatory for IL-2 induction (Jain et al, 1992;Luo et al, 1996;Northrop et al, 1993;Rooney et al, 1995). Since Tpl-2 activates NFAT as well as the MAPK pathway (Ceci et al, 1997;Tsatsanis et al, 1998), which is required for the activation of AP1 (Jain et al, 1993), we examined whether dominant negative mutants of several proteins transducing signals along these pathways inhibit the activation of the IL-2 promoter by Tpl-2. To this end, EL4 cells were cotransfected with an IL-2 promoter/ CAT reporter construct, a Tpl-2 expression construct and expression constructs of the dominant negative (DN) mutants Ha-ras N17, MEK1S218/222A, Raf1S621A and NFATcD418.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

View full text Add to dashboard Cite

The Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and su cient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/ 222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these ®ndings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells con®rmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFATD418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurindependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X L .

show abstract

Section: Resultsmentioning

confidence: 99%

“…NFAT is a complex factor composed of AP1 and NFAT components (Jain et al, 1993;Northrop et al, 1993). The NFAT component is heterogeneous and is represented by at least four protein isoforms encoded by di erent genes that are di erentially expressed in a variety of cell types.…”

Section: Introductionmentioning

confidence: 99%

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

View full text Add to dashboard Cite

show abstract

“…cJun interacts with the NF-kB subunit p65 to enhance binding to kB and AP-1 sites (Stein et al, 1993). Jun dimers and Jun/Fos heterodimers also form complexes with the T-cell transcription factor NFAT (Jain et al, 1993). The AP-1 and ATF/CREB transcription factors can form selective cross-family heterodimers with distinct DNA binding speci®cities.…”

mentioning

confidence: 99%

cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype

et al. 1999

View full text Add to dashboard Cite

We have previously demonstrated decreased Jun/AP-1 activity in the breast cancer cell line MCF-7 when compared to normal or immortalized mammary epithelial cells. In this paper, we overexpress Jun in MCF-7 cells (MCF7Jun) and demonstrate that it results in diverse biologic and biochemical changes, which mimic those seen clinically in breast cancer. Overexpression of Jun causes signi®cant alterations in the composition of AP-1, decreased junB and increased fra-1 expression and results in an increased biologic aggressiveness. MCF7Jun cells exhibit increased cellular motility, increased expression of a matrix degrading enzyme MMP-9, increased in vitro chemoinvasion and tumor formation in nude mice in the absence of exogenous estrogens. Furthermore, MCF7Jun cells are unresponsive to the growth stimulating e ects of estrogen and growth inhibitory e ects of tamoxifen. Analysis of the estrogen receptor (ER) expression and activity showed that the MCF7Jun cells have no detectable ER. MCF-7 cells overexpressing mutant forms of cJun were responsive to the growth stimulatory e ects of estrogen indicating that full-length cJun is required to acquire the estrogenindependent phenotype in breast cancer cells.

show abstract

“…These AP-1 factors can bind to the TRE (TPA-response element) sequence (Angel et al, 1987) and enhance gene expression. AP-1 factors also interact with other transcription factors including NF-kB (Stein et al, 1993), NF-AT (Jain et al, 1993) and glucocorticoid receptor (Jonat et al, 1990;Schule et al, 1990) to regulate gene expression.…”

mentioning

confidence: 99%

Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin

1998

View full text Add to dashboard Cite

Curcumin, a dietary pigment in curry, suppresses tumor initiation and tumor promotion. Curcumin is also a potent inhibitor for AP-1 and NF-kB activation. In this report, we show that curcumin inhibits JNK activation by various agonists including PMA plus ionomycin, anisomycin, UV-C, g radiation, TNF-a, and sodium orthovanadate. Although both JNK and ERK activation by phorbol 12-myristate 13-acetate (PMA) plus ionomycin were suppressed by curcumin, the JNK pathway was more sensitive. The IC 50 (50% inhibition concentration) of curcumin was between 5 ± 10 mM for JNK activation and was 20 mM for ERK activation. In transfection assays, curcumin moderately suppressed MEKK1-induced JNK activation; however, it e ectively blocked JNK activation caused by co-transfection of TAK1, GCK, or HPK1. Curcumin did not directly inhibit JNK, SEK1, MEKK1 or HPK1 activity. Although curcumin suppressed TAK1 and GCK activities at high concentrations, this inhibition cannot fully account for the JNK inhibition by curcumin in vivo. Our data suggest that curcumin may a ect the JNK pathway by interfering with the signaling molecule(s) at the same level or proximally upstream of the MAPKKK level. Taken together, the inhibition of the MEKK1-JNK pathway reveals a possible mechanism of suppression of AP-1 and NF-kB signaling by curcumin, and may explain the potent anti-in¯ammatory and anti-carcinogenic e ects of this chemical.

show abstract

The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun

Cited by 728 publications

References 28 publications

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype

Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin

Contact Info

Product

Resources

About