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*
Department of Molecular Pathology, Institute of Pathology, University of Würzburg, Würzburg, Germany;
Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany; and
Biomedical Research and Study Center, University of Latvia, Riga, Latvia
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, CD40 ligand, and Fas ligand
promoters/enhancers (see Ref. 4 for a recent review). It is likely that
NF-AT factors control also the promoter activity of further pro- and
antiapoptotic genes, genes regulating the cell cycle, and numerous
transcription factor genes (5, 6). This suggests that NF-AT factors not
only control the activation and proliferation but also the
differentiation and programmed death of T lymphocytes as well as
lymphoid and nonlymphoid cells.
The molecular cloning of four individual NF-AT cDNAs encoding the
factors NF-ATp (or NF-AT1), NF-ATc (or NF-AT2), NF-AT3, and NF-AT4 (or
NF-ATx) revealed several common structural features among the NF-AT
proteins and other transcription factors (4). One conspicuous
structural property the NF-AT factors share with Rel/NF-
B factors is
the Rel-like DNA binding domain of approximately 300 aa. In these
so-called Rel similarity domains (RSDs) the NF-AT factors exhibit
>60% homology among each other and 18–20% homology to the NF-B
factors. Several segments of the Rel similarity domain from NF-ATp, in
particular an octameric oligopeptide near the N-terminus, are highly
homologous to the corresponding DNA binding motifs of NF-B factors
(7), which is reflected in a common strand topology of Rel domains (8)
and the binding of NF-AT and NF-B factors to similar DNA motifs (4).
NF-ATp and NF-ATc are highly expressed in peripheral T cells and strongly activate the IL-2 and IL-4 promoters in transfection assays (4). This suggested that both factors play a very similar prominent role in gene induction upon T cell activation. However, inactivation of the NF-ATp and NF-ATc genes in mice resulted in contrasting effects on cell differentiation and activation. Inactivation of the NF-ATc gene led to severe defects in embryonic heart development and to the early death of embryos (9, 10). NF-ATc-/- thymocytes generated after injection of NF-ATc-/- ES cells into RAG-/- blastocystes showed severe developmental defects, while peripheral NF-ATc-/- T cells were defective in their proliferation and the production of Th2 lymphokines (11, 12). In contrast, NF-ATp-/- mice showed normal heart and thymus development, but accumulated preactivated T lymphocytes (13, 14, 15) and an increase in the synthesis of Th2 lymphokines and Th2-driven immune responses (16). Several of these features were even more pronounced in mice double deficient for NF-ATp and NF-AT4. The T cells of those double-deficient mice produce large amounts of the Th2-type lymphokines IL-4, IL-5, IL-10, and IL-13, suggesting a role for NF-ATp and NF-AT4 in controlling a major repressor for the concerted synthesis of these lymphokines in Th2 cells (11).
It is presently unknown which molecular events lead to the contrasting effects of NF-AT deficiency in vivo. Although NF-ATp and -c bind to very similar, if not identical, DNA motifs, they appear to control quite different sets of target genes. One mechanism leading to this effect might be the mode of NF-AT expression. Contrary to NF-ATp, which is not expressed in cardiac cells (4) (S. Chuvpilo, unpublished observations), NF-ATc is highly expressed in embryonic cardiac cells of mice, where it controls the generation of cardiac valves and septa 9–12 days after gestation (9, 10). While NF-ATp is constitutively expressed in T cells, B cells, and several nonlymphoid cells, NF-ATc is inducibly expressed in effector T cells (17). Another mechanism leading to the control of different target genes might be the cooperation of NF-AT factors with specific transcriptional activators and repressors, resulting in diverging transcriptional responses. To elucidate the transcriptional properties of NF-ATc proteins we have investigated the transcriptional function of C-terminal peptides of two NF-ATc isoforms.
Like other NF-AT factors, NF-ATc is expressed in multiple isoforms (17). This is due to alternate splice/polyadenylation events leading to the predominant synthesis of the longer NF-ATc isoforms, B and C, in naive T cells and the shorter isoform, A, in effector T cells. Isoforms B and C mainly differ from isoform A in the length of their C termini. While isoform B spans an additional stretch of 128 aa, isoform C contains this peptide and an extra stretch of 118 aa (17). We will show here that the 246-aa C-terminal peptide of isoform C spans a trans-activation domain, TAD-B,3 which along with the common N-terminal TAD-A controls the transcriptional activity of NF-ATc/C. In contrast, the C-terminal peptide in NF-ATc/B appears to act like a transcriptional repressor. We assume that these properties of NF-ATc isoforms B and C modulate their transcriptional activity in naive and other T cells where they are expressed in high concentrations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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All lymphoid cells were grown to a density of 2 x
105 cells/ml in RPMI medium containing 5% FCS. In
transient transfections of murine El4 T lymphoma cells 10 µg of DNA
was transfected into 2.5 x 107 cells using a
conventional DEAE-dextran transfection protocol. They were induced with
TPA (10 ng/ml), TPA plus ionomycin (T+I), or T+I and forskolin (5 µM)
as indicated. Human 293 embryonic kidney cells were grown in DMEM
containing 10% FCS. Eight to sixteen hours before transfection the
cells were diluted to 2 x 105 cells/2-ml dish. They
were transfected using a conventional Ca2+ phosphate
transfection protocol and induced with TPA (50 ng/ml), T+I, or T+I and
forskolin. Human umbilical cord blood (CB) and peripheral blood T
lymphocytes were isolated and induced with either T+I or mAbs against
CD3 (-T-Pan.Cells, clone 4B5, Boehringer Mannheim, Mannheim,
Germany) and CD28 (CLB-CD28, clone 15E8; CLB, Amsterdam, The
Netherlands). For -CD3 and CD28 Ab stimulation, cells were exposed
to panned -CD3 (3 µg/ml) and to soluble -CD28 Ab (1 µg/ml)
for the times indicated.
The secretion of IL-2 and IL-4 was determined by ELISAs using Cytoscreen immunoassay kits (BioSource International, Camarillo, CA).
Transient transfection assays of NF-ATc cDNAs
The NF-ATc cDNA expression vectors pRSV-NF-ATc/A and pRSV-NF-ATc/B were constructed by the insertion of complete cDNAs into the multiple cloning site of a pBluescript KS+ vector containing RSV LTR and SV40 splice/poly(A) fragments. Due to the very poor expression of the original expression vector pRSV-NF-ATc/C, a novel expression vector was constructed by replacing the Bsp68I/BamHI fragment in pRSV-NF-ATc/B with that of the original NF-ATc/C vector. Thus, the pRSV NF-ATc/C expression vector used throughout this work contains the 5' region of NF-ATc/B and the 3' portion of NF-ATc/C spanning 943 aa (instead of 930 in NF-ATc/C). Therefore, this vector allows study of the contribution of the very C-terminal portion of NF-ATc/C in the context of NF-ATc/B. It is likely that such an NF-AT isoform is also expressed in vivo (see the structure of isoform NF-ATc.ß described in 18). For the activation of reporter genes, a 2- to 5-fold excess of expression plasmids was transfected into 293 cells along with 50 ng of promoter/luciferase (or CAT) gene constructs.
RNase protection assays
For RNase protection assays, total RNA was extracted using TRIzol reagent (Life Technologies, Gaithersburg, MD). The RNA was processed according to PharMingen’s RiboQuant protocol (San Diego, CA), using the human cytokine hCK-1 multiprobe template set.
Western blot assays and preparation of nuclear proteins
In Western blot assays, proteins were separated on 8 or 10% PAA SDS gels followed by electrophoretic transfer onto BA 85 nitrocellulose membranes (Schleicher & Schuell, Keene, NH) overnight and immunodectection with the NF-ATc-specific mAb 7A6 (19), designated mAb-A, or a polyclonal Ab, pAb-B, raised against the extra C-terminal peptide in NF-ATc/B (17). Nuclear proteins from lymphoid cells were prepared as previously described (20), except that Nonidet P-40 was omitted for the preservation of cell nuclei. The swollen cells were disrupted by passing them 10 times through an injection needle (26 gauge, 0.375 in.). After centrifugation, the nuclear pellet was washed three times with large volumes of swelling buffer. Immunodetections were performed using the enhanced chemiluminescence detection system (Amersham, Aylesbury, U.K.) according to the instructions of the manufacturer.
Gal4 fusion proteins and trans-activation assays
For determination of the trans-activating properties of NF-ATc peptides, expression vectors for the overexpression of Gal4/NF-ATc fusion proteins were constructed on the basis of the RSV-LTR-controlled Gal4 vector pABgal linker (21) encoding the 1–147 aa of the yeast transcription factor Gal4, which contains the DNA binding and dimerization domains of Gal4. The following vectors were constructed: Gal4/TAD-A containing 1–205 aa from NF-ATc/A, and a PCR product encoding the first 301 aa of NF-ATc, cut by NcoI and cloned as a blunt end fragment into the filled BamHI site of pABgal linker DNA. In a similar way pGal4/TAD-B constructs were obtained by cloning blunt end PCR products from NF-ATc/C into the filled BamHI site of pABgal linker plasmid, resulting in the constructs Gal4/TAD-B (containing aa 690–930), Gal4/TAD-B120 (aa 690–812), Gal4/TAD-B30 (aa 690–720), Gal4/TAD-B90 (aa 723–812), and Gal4/TAD-Bpro (aa 813–930). The structures of all plasmids were verified by sequencing. All DNA work was performed using enzymes from MBI Fermentas (Vilnius, Lithuania). Transient expression levels of Gal4/NF-ATc fusion proteins in 293 and El4 cells were determined in EMSAs using a Gal4 binding site as a probe (22).
To test the transacting properties of C-terminal peptides in yeast cells, the entire 3' DNA fragment of NF-ATc/C and subfragments were inserted into the construct pAS2–1 (Matchmaker two-hybrid system 2, Clontech, Palo Alto, CA). Three separate yeast colonies (of strain Y190) transformed with the DNA constructs were used to inoculate 5 ml of tryptophan drop out medium (Clontech). After overnight culture at 30°C, 2-ml portions were used to inoculate 5 ml of YPD medium (Clontech), and cells were grown for 3–5 h to an OD600 of 0.5–0.8. After centrifugation of 1.5 ml, the pelleted yeast cells were washed and resuspended in 300 µl in buffer Z (100 mM Na2HPO4, 40mM NaH2PO4, 10mM KCl, and 1 mM MgSO4, pH 7). One hundred microliters of cells were lysed by freezing in liquid nitrogen and thawing. Buffer Z with 2-ME (0.7 ml), 160 µl O-nitrophenyl ß-D-galactopyranoside, and the samples were cultured at 30°C. After the yellow color developed, 0.4 ml of 1 M Na2CO3 was added, the samples were centrifuged, and the supernatants were used for the OD420 measurements. The ß-galactosidase units were calculated according the formula: ß-galactosidase units = 1000 x OD420/(t x V x OD600), where t is the elapsed time of incubation in minutes, V is 0.1 ml x concentration factor, and OD600 is A600 of 1 ml of culture.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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IL-2 is the first lymphokine synthesized after stimulation
of naive T lymphocytes from human CB (23). This is shown in Fig. 1
, A and B, where
the synthesis of IL-2 RNA and secretion of IL-2 were detected after
induction of CB T cells by TPA and ionomycin (T+I) for 6 and 12 h,
respectively. Apart from IFN-
and minute amounts of IL-5, no further
lymphokine RNAs were synthesized under these conditions. In contrast,
treatment of resting human peripheral blood T lymphocytes with T+I led
to a rapid synthesis of numerous lymphokine RNAs. In addition to the
massive synthesis of IL-2 and IFN- RNAs the synthesis of Th2-type
lymphokines IL-4, IL-5, and IL-10 was detected (Fig. 1A, lanes 4–7). A similar, albeit much weaker,
synthesis of lymphokine RNAs was also observed after stimulation by
CD3 and CD28 Abs (Fig. 1A, lanes 8–10).
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C, untreated CB and PBL T
cells did not contain any detectable nuclear NF-ATc. Stimulation of CB
T cells with T+I led to the nuclear appearance of NF-ATc isoforms B and
C after 6–12 h, whereas the same treatment of PBL T cells resulted in
the detection of these large NF-ATc proteins after 2 h. After
6 h, NF-ATc isoform A of about 90 kDa became detectable. A
moderate nuclear accumulation of NF-ATc proteins was observed when PBL
T cells were treated with CD3-CD28 Abs. Thus, the onset and extent
of lymphokine synthesis and secretion correlate well with the nuclear
appearance of NF-ATc proteins. However, while the concentrations of
lymphokine RNAs decreased in PBL T cells after stimulation for 6
h, the concentrations of nuclear NF-ATc proteins increased, suggesting
a role for NF-ATc in the control of promoters in addition to those of
lymphokine genes. The extra C-terminal peptides of NF-ATc isoform C contain an additional trans-activation domain
We have shown previously that in numerous types of T cells NF-ATc is expressed in the three isoforms, A, B, and C, which differ in the length of their C termini (17). While these investigations revealed the mode of NF-ATc isoform synthesis, they did not provide information on the function of extra C-terminal peptides.
The schematic structure of the NF-ATc isoforms A and C is shown in Fig. 2A. The extra C-terminal
peptides in NF-ATc/C spanning the amino acids from positions 685–930
(see Fig. 2B) exhibit sequence homologies of 30.6% to those
in NF-ATp (24). The more proximal region (aa 685–813 in NF-ATc/C)
exhibits 36.7% sequence homology. The NF-ATc/C-specific domain (aa
814–930) contains 20.5% Pro residues and shows a very poor similarity
to NF-ATp in its proximal half, while the last 32 C-terminal amino
acids exhibit a strong homology to NF-ATp, in particular to isoform C
(24). They span an identical decapeptide of aa 911–920 (boxed in Fig. 2B) that contains three leucine/isoleucine residues and,
therefore, could represent a nuclear export signal (25). In a very
similar version it was identified as part of C-terminal TAD of NF-ATx1
(26).
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, A and
C). The shorter C-terminal peptides, in particular
TAD-B30 and TAD-B120, showed a measurable,
albeit weak, activity in El4 cells. In contrast, TAD-B90
was completely inactive (Fig. 2C). Similar results were
obtained using 293 cells. While in these cells, TAD-B was as active as
in El4 cells; all shorter peptides were found to be uninducible and
suppressed the weak activity of Gal41–147 peptide (Fig. 2D).
We also tested the transcriptional activity of C-terminal peptides in
yeast cells using a quantitative ß-galactosidase assay and the TAD of
the basic helix-loop-helix factor E12 for comparison (probably due to
its dependence on the cofactor CBP/p300, TAD-A remained inactive in
yeast cells). In these cells, TAD-B showed approximately 16% the
activity of E12 TAD. Three shorter peptides, TAD-B30,
TAD-B120, and TAD-Bpro, exhibited somewhat
weaker activity, whereas TAD-B90 was again inactive, as in
El4 T cells and 293 cells (Fig. 2E). Taken together, these
results indicate the existence of a second trans-acting
domain in NF-ATc/C,TAD-B that appears to be composed of positively
acting (present in TAD-B30, TAD-B120, and
TAD-Bpro) and negatively acting elements (in
TAD-B90).
The activity of TAD-B is induced by various stimulators of T cells
The striking difference in the extent of TPA-mediated
stimulation between TAD-A and TAD-B prompted us to investigate whether
this is also true for other inducers of T cells. As shown in Fig. 3A (and Fig. 2, C
and D) TPA is a quite strong inducer of TAD-A, leading to a
5- to 10-fold increase in its activity in El4 cells, whereas a 2- to
3-fold increase was observed for TAD-B. In contrast, a rise in
intracellular Ca2+, as mediated by ionomycin
treatment, increased neither TPA-mediated TAD-A nor TAD-B induction,
and CsA, an inhibitor of Ca2+-dependent calcineurin
activity, was without effect on the induction of both TADs by T+I. On
the other hand, irradiation of El4 T cells by UV light or treatment
with methyl methane sulfonate along with TPA markedly increased the
induction of both TADs (Fig. 3A). These results illustrate
remarkable similarities in the induction of both TADs from NF-ATc and
suggest a concerted activation of TAD-A and TAD-B, which differ
remarkably in strength but not in mode of activation.
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B), which overlaps with a
binding site for calcineurin (28). To determine whether TAD-B is also
phosphorylated after TPA treatment we performed solid phase protein
kinase assays. In these assays whole protein extracts from El4 cells
induced by TPA, UV light irradiation, or both treatments were used to
phosphorylate chimeric GST/TAD-A and -B proteins coupled to glutathione
agarose beads. As shown in Fig. 3B, TPA treatment of cells
led to a marked increase in constitutive TAD-A phosphorylation, whereas
no phosphorylation could be detected for TAD-B. UV irradiation alone or
in combination with TPA led to only a marginal, if any, increase in
constitutive or TPA-mediated TAD-A phosphorylation. Both treatments
were without effect on the phosphorylation state of TAD-B (Fig. 3B).
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To test the transcriptional activity of individual NF-ATc
proteins we cotransfected expression vectors for NF-ATc/A, -B, or -C
together with a variety of promoter/reporter gene constructs into 293
cells, which express only minor amounts of endogenous NF-ATc (not
shown). As shown in Fig. 4, A and B, all three
NF-ATc isoforms were properly expressed and translocated into the
nuclei as proteins of approximately 90, 110, and 140 kDa, respectively.
Dephosphorylation of nuclear proteins led to an increase in their
electrophoretic mobility, indicating phosphorylation of all three
isoforms in these cells (Fig. 4C). All three NF-ATc proteins
stimulated the inducible activation of luciferase reporter genes driven
by four copies of the distal NF-AT site (Pu-bd) from the
murine IL-2 promoter (2) or three copies of Pu-bB from the
murine IL-4 promoter (Fig. 4, D and E) (29). In
all transfection assays, NF-ATc/B was the weakest
trans-activator (Fig. 4D), whereas NF-ATc/C
appeared to be the strongest NF-ATc, being 2-fold stronger than
NF-ATc/A in the activation of Pu-bd and 3-fold stronger in
Pu-bB activation (Fig. 4E).
We also tested the activities of individual NF-ATc isoforms on the
induction of the IL-2, IL-4, and IL-5 promoters after transfection into
293 cells. To test the effect of NF-ATc proteins on the TPA-mediated
induction of the murine IL-2 and IL-4 promoters, luciferase and CAT
reporter gene constructs governed by either the IL-2 or IL-4 promoter
were cotransfected with NF-ATc expression vectors into the same batch
of cells. As shown in Fig. 5A,
all three isoforms increased the induction of both promoters, in
particular after stimulation with TPA. In these assays, NF-ATc/B again
appeared to be the weakest trans-activator, leading to a 2-
to 5-fold weaker activation of the IL-2 and IL-4 promoters than
NF-ATc/A. Surprisingly, NF-ATc/A exerted the same or even a stronger
effect on the induction of both promoters as the longest isoform
NF-ATc/C carrying two TADs (Fig. 5A). Very similar, albeit
less detailed, data on the different transcriptional potencies of
NF-ATc isoforms were also obtained after transfection into El4 T cells
(data not shown).
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B, cotransfections of an IL-5 promoter-driven
luciferease gene with vectors expressing the three NF-ATc isoforms with
GATA-3 and Ets-1 drastically enhance the T+I- and, in particular, the
T+I- and forskolin-mediated induction of the IL-5 promoter. However, no
marked differences among the three NF-ATc isoforms were detected when
they were cotransfected with GATA-3 or Ets-1 alone or upon
cotransfection with GATA-3 and Ets-1 together. These results indicate
that the NF-ATc isoforms differ in their transcriptional activity
depending on the promoter context. Concluding remarks
All members of NF-AT transcription factor family are expressed in multiple isoforms. This has been shown in detail for NF-ATp and NF-AT4/x, which are expressed in several isoforms in T lymphocytes and other cells (24) (26). However, in contrast to the NF-ATc isoforms, all three NF-ATp isoforms are similar in length or even longer than NF-ATc/C, the longest NF-ATc isoform. A short isoform lacking an extra C-terminal peptide, as does NF-ATc/A, has also been described for NF-AT4 (32), but it remains to be shown whether it is inducibly synthesized like NF-ATc/A. The NF-ATp isoforms share a C-terminal QP-rich stretch of approximately 220 aa that shows >30% homology to the C-terminal NF-ATc/C peptide and is able to act as a TAD (33). Such a second TAD has also been identified within the C-terminal portion of the longest isoform of NF-AT4/x, designated NFATx1 (26). Thus, the existence of a C-terminal TAD is not a peculiarity of the long NF-ATc isoform C but is a typical component of numerous NF-AT proteins.
Using a panel of NF-ATc-specific Abs Lyakh et al. (34) observed in peripheral human T cells the expression of three prominent NF-ATc proteins very similar in length to the three NF-ATc isoforms we have cloned. An NF-ATc isoform similar to isoform B and designated NF-ATc.ß was isolated from a human Burkitt lymphoma cDNA library and described to posses a specific C-terminal peptide missing any homology to NF-ATp (18). However, introduction of 2 bp into the NF-ATc.ß sequence (at positions 2334 (C) and 2451 (G); numbering according to 18) leads to a sequence identical to the NF-ATc/B peptide and, therefore, shares about 36% sequence homology to the C terminus of NF-ATp.
The identification of TAD-B in NF-ATc/C raises the question of which roles these isoforms play in gene control in T lymphocytes and other cells where they are highly expressed at different relative levels. The conspicuous differences between the NF-ATc isoforms in activation of the IL-2 and IL-4 promoters, on the one hand, and of the IL-5 promoter, on the other, suggest important functional roles of individual isoforms in promoter control. Several lines of evidence indicate that threshold levels of NF-AT play a crucial role in the induction of promoters in T cells (17, 36). In addition, due to the different transcriptional capacities of NF-AT isoforms, changes in isoform composition will result in marked differences in specific transcriptional activity of nuclear NF-ATc. Apart from the analysis of NF-AT-driven promoters other than the typical lymphokine promoters, the establishment of mouse mutants defective in the synthesis of one or the other NF-ATc isoform will allow study of the function of individual NF-ATc proteins in detail.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Edgar Serfling, Department of Molecular Pathology, Institute of Pathology, University of Würzburg, D-97080 Würzburg, Germany. E-mail address:
3 Abbreviations used in this paper: TAD, trans-activation domain; TPA, 12-O-tetradecanoyl 12-phorbol 13-acetate; T+I, TPA plus ionomycin; CB, cord blood; RSV, Rous sarcoma virus; LTR, long terminal repeat; CAT, chloramphenicol acetyltransferase; PAA, polyacrylamide; CsA, cyclosporin A.
Received for publication February 1, 1999. Accepted for publication April 6, 1999.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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 J. C. Keen, L. Sholl, M. Wills-Karp, and S. N. Georas Preferential Activation of Nuclear Factor of Activated T Cells c Correlates with Mouse Strain Susceptibility to Allergic Responses and Interleukin-4 Gene Expression Am. J. Respir. Cell Mol. Biol., January 1, 2001; 24(1): 58 - 65. [Abstract] [Full Text]
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C.-W. Chow, C. Dong, R. A. Flavell, and R. J. Davis c-Jun NH2-Terminal Kinase Inhibits Targeting of the Protein Phosphatase Calcineurin to NFATc1 Mol. Cell. Biol., July 15, 2000; 20(14): 5227 - 5234. [Abstract] [Full Text]
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