The Duration of Nuclear Residence of NFAT Determines the Pattern of Cytokine Expression in Human SCID T Cells

Feske, Stefan; Draeger, Ruth; Peter, Hans‐Hartmut; Eichmann, Klaus; Rao, Anjana

doi:10.4049/jimmunol.165.1.297

Cited by 122 publications

(57 citation statements)

References 65 publications

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“…PMA and ionomycin are potent activators of calcineurin and cause dephosphorylation of NFAT proteins. CysA and FK506 are potent inhibitors of calcineurin phosphatase activity and restore PMA-and ionomycin-induced NFAT dephosphorylation and, thus, NFAT-mediated gene induction (46,47). Our results show that NFAT4 phosphorylation was significantly reduced after stimulation of Jurkat T cells with PMA and ionomycin.…”

Section: Calmodulin (Cam) and Camkii Regulate Lps-and Tnf-␣-induced Csupporting

confidence: 59%

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Distinct Role of Calmodulin and Calmodulin-dependent Protein Kinase-II in Lipopolysaccharide and Tumor Necrosis Factor-α-mediated Suppression of Apoptosis and Antiapoptotic c-IAP2 Gene Expression in Human Monocytic Cells

Mishra

Gee

et al. 2005

Journal of Biological Chemistry

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Section: Calmodulin (Cam) and Camkii Regulate Lps-and Tnf-␣-induced Csupporting

confidence: 59%

“…3D). The biological activity of CysA and FK506 was determined by analysis of NFAT4 expression in Jurkat T cells as described (46,47). PMA and ionomycin are potent activators of calcineurin and cause dephosphorylation of NFAT proteins.…”

Section: Calmodulin (Cam) and Camkii Regulate Lps-and Tnf-␣-induced Cmentioning

confidence: 99%

Distinct Role of Calmodulin and Calmodulin-dependent Protein Kinase-II in Lipopolysaccharide and Tumor Necrosis Factor-α-mediated Suppression of Apoptosis and Antiapoptotic c-IAP2 Gene Expression in Human Monocytic Cells

Mishra

Gee

et al. 2005

Journal of Biological Chemistry

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“…For staining suspension cells (T and B cells), the procedures were also as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

IκB Family Members Function by Different Mechanisms

Tam

Sen

2001

Journal of Biological Chemistry

114

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The IB family of proteins regulates NF-B-dependent transcription by inhibiting DNA binding and localizing these factors to the cell cytoplasm. IB␣ does this by shifting the balance between nuclear import of Rel proteins and their export from the nucleus. Here we show that, unlike IB␣, IB␤ and IB⑀ appear to sequester p65 or c-Rel in the cytoplasm by inhibiting nuclear import. Furthermore, because IB␤ does not undergo nucleocytoplasmic shuttling, it cannot remove nuclear proteins like IB␣ does. We conclude that the mechanism of action differs among IB family members.The NF-B 1 /Rel family of transcription factors plays a central role in immune and inflammatory responses (1). In most cell types these proteins are sequestered in the cell cytoplasm complexed to a family of inhibitory IB proteins (2, 3). Cellular activation results in IB degradation, which leaves the DNAbinding protein free to translocate to the nucleus and activate gene expression. Because of the widespread effects of NF-B activation, its localization in the cytoplasm must be strictly maintained. IB␣-deficient mice are a striking example of the importance of NF-B sequestration in the cytoplasm; these mice die of a wasting disease that has been attributed to tumor necrosis factor-␣ production (4, 5). Nuclear factor-B has also been detected in several diseased tissues, where it has been proposed to contribute to the pathology in part by inhibiting apoptosis (6, 7).The association of Rel with IB␣ has been proposed to hide the NLS of Rel proteins (8, 9), thereby precluding nuclear entry of the transcription factor. In addition to hiding the NLS, association with IB␣ also inhibits DNA binding by NF-B. Thus, association of NF-B with IB ensures that NF-B-dependent gene transcription occurs only when cells are stimulated appropriately.Recently, IB␣ has been shown to shuttle between the nucleus and the cytoplasm. Nuclear entry is mediated by a nonclassical NLS located in the second ankyrin repeat of IB␣ (10 -12), and nuclear export is determined by a CRM1-dependent nuclear export sequence located in the N-terminal domain preceding the first ankyrin domain (13-15). A second nuclear export sequence has been identified at the C terminus of IB␣, but its functional significance is unclear at present (16,17). The observation that cytoplasmic sequestration of p65⅐RelA also required nuclear export was unexpected and led to a reassessment of the existing sequestration model. We and others (13-15) have proposed that the cytoplasmic location of Rel proteins by IB␣ is a dynamic process that depends on the active export of Rel⅐IB␣ complexes out of the nucleus.In our earlier studies we also showed that IB␤ and IB⑀, unlike IB␣, do not shuttle via the CRM1 pathway. Specifically, the subcellular distribution of GFP-IB␤ or GFP-IB⑀ in yeast was not affected by a mutation in the CRM1 gene, and leptomycin B (LMB) treatment did not alter the location of these proteins in transiently transfected mammalian cells. In addition, we did not detect an association between CRM1 protein and...

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“…Consequently, NFAT-dependent transcription is highly dynamic and exquisitely sensitive to changes in the intracellular calcium concentration (11,12). This aspect of NFAT regulation is likely to be significant, since both the extent and duration of NFAT activity have recently been shown to influence the qualitative pattern of NFAT-dependent gene expression induced during T cell activation (13).…”

mentioning

confidence: 99%

A Constitutively Active NFATc1 Mutant Induces a Transformed Phenotype in 3T3-L1 Fibroblasts

Neal

Clipstone

2003

Journal of Biological Chemistry

128

146

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The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway is best known for its role in T lymphocyte activation. However, it has become increasingly apparent that this signaling pathway is also involved in the regulation of cell growth and development in a wide variety of different tissues and cell types. Here we have investigated the effects of sustained NFATc1 signaling on the growth and differentiation of the murine 3T3-L1 preadipocyte cell line. Remarkably, we find that expression of a constitutively active NFATc1 mutant (caNFATc1) in these immortalized cells inhibits their differentiation into mature adipocytes and causes them to adopt a transformed cell phenotype, including loss of contact-mediated growth inhibition, reduced serum growth requirements, protection from growth factor withdrawal-induced apoptosis, and formation of colonies in semisolid media. Furthermore, we find that caNFATc1-expressing cells acquire growth factor autonomy and are able to proliferate even in the complete absence of serum. We provide evidence that this growth factor independence is caused by the NFATc1-dependent production of a soluble heat-labile autocrine factor that is capable of promoting the growth and survival of wild type 3T3-L1 cells as well as potently inhibiting their differentiation into mature adipocytes. Finally, we demonstrate that cells expressing caNFATc1 form tumors in nude mice. Taken together, these results indicate that deregulated NFATc1 activity is able to induce the immortalized 3T3-L1 preadipocyte cell line to acquire the well established hallmarks of cellular transformation and thereby provide direct evidence for the oncogenic potential of the NFATc1 transcription factor.

show abstract

The Duration of Nuclear Residence of NFAT Determines the Pattern of Cytokine Expression in Human SCID T Cells

Cited by 122 publications

References 65 publications

Distinct Role of Calmodulin and Calmodulin-dependent Protein Kinase-II in Lipopolysaccharide and Tumor Necrosis Factor-α-mediated Suppression of Apoptosis and Antiapoptotic c-IAP2 Gene Expression in Human Monocytic Cells

Distinct Role of Calmodulin and Calmodulin-dependent Protein Kinase-II in Lipopolysaccharide and Tumor Necrosis Factor-α-mediated Suppression of Apoptosis and Antiapoptotic c-IAP2 Gene Expression in Human Monocytic Cells

IκB Family Members Function by Different Mechanisms

A Constitutively Active NFATc1 Mutant Induces a Transformed Phenotype in 3T3-L1 Fibroblasts

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