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Previous Article | Next Article 
Molecular and Cellular Biology, November 2005, p. 9249-9258, Vol. 25, No. 21
0270-7306/05/$08.00+0 doi:10.1128/MCB.25.21.9249-9258.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan,1 Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan,2 National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan,3 Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan4
Received 29 April 2005/ Returned for modification 27 May 2005/ Accepted 2 August 2005
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ABSTRACT |
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INTRODUCTION |
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A number of viruses encode viral FLIP (v-FLIP), which contains two tandemly repeated DEDs only (6, 18, 50). v-FLIP robustly blocks the Fas-mediated apoptosis-inducing signal by forming homophilic interactions with DEDs of FADD and/or caspase 8 (6, 18, 49) and has been considered to play a role in allowing virally infected cells to escape immune surveillance, since this utilizes Fas-induced apoptosis. Hence, the function of v-FLIP may be to allow some viruses to continue to proliferate, by enhancing the survival of virus-infected host cells. A number of viruses have been reported to encode v-FLIP, including E2 (bovine herpesvirus 4) (18, 49), E8 (equine herpesvirus 2) (6, 18, 49), ORF16 (saimirine herpesvirus) (49), K13/ORF71 (human herpesvirus 8) (18, 49), and MC159 (molluscum contagiosum poxvirus) (6, 18, 49), and all these viruses, other than MC159, are products of gammaherpesvirus.
Some recent evidence has suggested that FLIP exhibits a regulatory function for cell proliferation and differentiation, in addition to an inhibitory activity against Fas-induced apoptosis. c-FLIPL has been reported to promote activation of nuclear factor 
B (NF-B) and extracellular signal-regulated kinase (22). v-FLIP K13 was shown to activate the canonical and alternative NF-B pathways, but other v-FLIPs do not share such activity (9, 30). K13 was also reported to activate the c-jun N-terminal protein kinase pathway (2), and, furthermore, to induce cellular survival, proliferation, and transformation through transcriptional upregulation of antiapoptotic and growth-promoting effector molecules through the activation of NF-B, while neither E8 nor MC159 exhibits these biological activities (12, 15, 30, 46).
We have previously reported that transgenic (Tg) mice expressing v-FLIP E8 in thymocytes exhibit thymic atrophy arising from a reduction of thymocyte number (36). The thymic obsolescence might be a result of E8-induced suppression of T-cell development in the early stage of the transition from the double negative 3 (DN3) to the DN4 stage (36), where the number of thymocytes is known to increase. Interestingly, thymocytes of the Tg mice retained their ability to proliferate in response to in vitro stimulation with anti-CD3 and anti-CD28 monoclonal antibodies (MAbs). Taking these observations together, we concluded that E8 expressed in thymocytes acts as a negative regulator for their differentiation and/or proliferation in vivo, although the complete molecular mechanism underlying the function of E8 remains to be determined.
Wnt signaling is thought to be important for embryogenesis and ontogenesis (29) and has been reported to play an essential role in the differentiation of immature thymocytes from the DN to the double positive (DP) stage (14, 45). Wnt signaling is triggered by the binding of Wnt family ligands to their receptors, which are referred to as the Frizzled receptor family, and then transmitted to the Dishevelled protein, which inactivates glycogen synthase kinase-3ß (GSK-3ß) (55). ß-Catenin is usually phosphorylated by GSK-3ß before undergoing degradation through the ubiquitin-proteasome pathway (1). Wnt-induced inactivation of GSK-3ß stabilizes ß-catenin, causing its accumulation in the cytosol and subsequent transfer into the nucleus, where it binds to T-cell factor (TCF) family transcription factors, inducing the expression of Wnt-specific target genes that regulate cellular proliferation and/or differentiation (8, 24, 37). Staal et al. have reported that Wnt signaling is involved in the development of immature thymocytes from DN to DP, in which TCF-1 and lymphocyte enhancer factor 1 (LEF-1) are required to induce differentiation (45). Gounari et al. have studied Tg mice with stabilized ß-catenin in thymocytes and showed that the total cell numbers in the thymus decreased and that differentiation was suppressed between the DN3 and DN4 stages (14).
Tg mice with stabilized ß-catenin in thymocytes demonstrated a similar phenotype to that in our E8 Tg mice (36). For this reason, we hypothesized that E8 might act in the Wnt signaling pathway. In this study, E8 was shown to dramatically enhance Wnt signaling in various cell lines downstream of Wnt-induced stabilization of ß-catenin. In addition, marked enhancement of Wnt signaling by expression of v-FLIP E8 allowed the detection of Wnt signaling that induced dramatic growth retardation in untransformed cell lines but not in transformed cell lines in vitro.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (pB-luc) and its control reporter plasmid without the B enhancer sequence (pdN-luc) were gifts from J. Fujisawa (Kansai Medical College, Osaka, Japan). The TCF-luciferase reporter plasmid (pTCFwt-luc) with seven tandem repeats of the TCF response element and a mutant reporter plasmid (pTCFmt-luc) (52) were kindly provided by M. Hijikata and K. Shimotohno (Kyoto University). pRL-TK, used for the internal control in the dual luciferase assay, was purchased from Promega. The dominant negative mutant of TCF4E (TCF4E N80), which lacks a DNA-binding domain, ICAT, and constitutively stabilized ß-catenin, in which Ser33 was replaced by Tyr (ß-catenin S33Y), were expressed as the vectors pMKITNeo-FLAG-N80 (40), pcDNA3.1-FLAG-ICAT (47), and pMKITNeo-ß-catenin S33Y (25), respectively. The expression vectors for human c-FLIP and green fluorescent protein (GFP) were kindly provided by K. K. Lee (Kyoto University) and K. Umezono (Kyoto University), respectively. Preparation of Wnt3a-conditioned medium. Conditioned medium containing Wnt3a and control medium were prepared by cultivation of L cells stably expressing soluble Wnt3a (Wnt3a/L) and control cells (neo/L), respectively, as described previously (41).
Cell culture and transfection. BALB/3T3, Rat-1, 293, 293T, KB, U2OS, wild-type mouse embryonic fibroblast (MEF), caspase 8–/– MEF (39), and FL cells were cultured in Dulbecco's modified Eagle's medium (Nacalai Tesque Inc.) supplemented with 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin, and 100 µg/ml streptomycin at 37°C in 5% CO2. Cells in six-well plates or 10-cm dishes were transfected with 1 µg/well or 4 µg/dish of expression vectors, respectively, using Lipofectamine Plus reagent (Invitrogen), in accordance with the manufacturer's instructions.
Quantification of cell viability. KB cells in 6-well plates transfected with expression vectors for v-FLIP (0.8 µg/well) and GFP (0.2 µg/well) were seeded in 96-well plates. After 2 days of cultivation, cells were stimulated with 500 ng/ml of anti-Fas antibody, CH-11, together with 1 µg/ml of cycloheximide. To quantify cell viability in the 96-well plates, the number of GFP-positive cells per field of an immunofluorescence microscope were counted after 2 days of cultivation, as described previously (23).
Dual luciferase assay. Cells in six-well culture plates were transfected with 1 µg/well pME18s, encoding v-FLIP, and 0.2 µg/well pTCFwt-luc or pTCFmt-luc, together with 0.02 µg/well pTK-RL. The total amount of DNA for each transfection was adjusted to 1.22 µg/well by adding empty vectors. Three hours after transfection, cells were reseeded in 48-well tissue culture plates, and cultured for around 18 h. Cells were then treated with conditioned medium containing soluble Wnt3a (Wnt3a/L-CM) or control medium (neo/L-CM) for 12 to 24 h, and a luciferase assay was performed using a dual luciferase assay kit (Promega), in accordance with the manufacturer's instructions. All data were expressed as means ± standard deviations (SD) (n = 3).
Concentration of cells expressing the exogenous gene. A MACS system (Miltenyi Biotec) was utilized to concentrate cells expressing the exogenous gene. A truncated form of the mouse interleukin-3 receptor ß-chain, tAic-2A (21), was used as a marker; this protein does not introduce any signaling in the cells in which it is expressed, because it lacks an intercellular domain. BALB/3T3 cells were transfected with an expression vector for E8 or an empty vector, together with vectors for tAic-2A and GFP. After treatment with Wnt3a/L-CM or neo/L-CM, cells were incubated with rat anti-Aic-2 MAb (58) followed by magnetic-bead-labeled mouse anti-rat immunoglobulin G Ab (Miltenyi Biotec) and then applied to a MidiMACS MS separation column according to the manufacturer's instructions.
Western blotting. Cells were lysed in ice-cold lysis buffer (20 mM Tris HCl, pH 7.4, containing 10% glycerol, 1% Triton X-100, 150 mM NaCl, and 1 mM EDTA) with protease inhibitor cocktail tablets (Roche). The lysate was resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analyzed by Western blotting, as previously described (27).
Colony formation assay. Cells in 6-well plates were cotransfected with 0.9 µg/well and 0.1 µg/well of the expression vectors for E8 and a neomycin resistance gene, respectively, and seeded in 24-, 12-, or 6-well plates immediately after transfection. Cells were then cultured with Wnt3a/L-CM or neo/L-CM, both of which contained 0.5 to 1.0 mg/ml of G418 (Nacalai Tesque Inc.), for 10 to 21 days. The culture medium was replaced every 2 days with fresh Wnt3a/L-CM or neo/L-CM containing G418. Colonies formed as G418-resistant cells were stained with Giemsa staining solution, or the cell number was determined after suspension following treatment with trypsin.
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RESULTS |
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B in BALB/3T3 cells, while the other two v-FLIPs, expression levels of which were much higher than that of K13 (Fig. 1D), did not activate NF-B (Fig. 1B), as previously reported (9, 12, 28).
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B-induced transcriptional activity, respectively, but that MC159, which is derived from poxvirus, failed to either activate NF-B or enhance Wnt signaling. We next analyzed whether the Wnt signal-enhancing activity of E8 is generally observed in a wide variety of cell lines (Fig. 2A). We examined Rat-1, 293, 293T, KB, U2OS, and MEF cells, which are sensitive to stimulation by Wnt3a. All the cells examined showed similar sensitivities to E8-mediated enhancement of Wnt3a-induced signaling.
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E8 enhances the Wnt-induced canonical signaling pathway. Transcriptional activity of TCF is usually suppressed in the absence of Wnt signals (48). Once Wnt signaling begins, stabilization of ß-catenin is induced, and the stabilized ß-catenin forms a complex with TCF in the nucleus, with the complex subsequently inducing Wnt-specific transcription. To verify whether E8 stimulates this Wnt/ß-catenin signal, which is referred to as the canonical Wnt signal, we tested the effects of two inhibitory proteins which directly suppress the association of ß-catenin and TCF on E8-induced stimulation of Wnt signaling. One is a ß-catenin-binding protein called ICAT, which blocks the interaction between ß-catenin and TCF (47). The other is a dominant negative mutant of TCF4E, termed TCF4E N80, which lacks the DNA binding region of TCF4E (26, 40). TCF4E is a member of the TCF/LEF family and may act downstream of Wnt3a, especially in fibroblasts (17, 38). We analyzed whether these inhibitory molecules suppressed the E8-induced activation of TCF-directed luciferase activity after cultivation with or without Wnt3a in BALB/3T3 cells. As shown in Fig. 3A, both TCF4E N80 and ICAT strongly inhibited Wnt3a-induced transcription in cells transfected either with or without the E8 expression vector. Thus, the interaction of ß-catenin and TCF plays an essential role in E8-mediated intensification of Wnt3a-induced signaling.
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Comparison of Wnt signal-enhancing activities of v-FLIP E8 and c-FLIPL in 293T cells. Although we tried to analyze the effects of c-FLIPS and c-FLIPL on Wnt signaling in BALB/3T3, KB, and other cell lines, it proved impossible to accurately assess the effect of c-FLIP because the expression of c-FLIP itself provoked apoptosis in these cells, as previously reported (13, 16, 19, 43). However, 293T cells appeared to be insensitive to c-FLIP-induced apoptosis, thereby allowing evaluation of c-FLIP activity on Wnt signaling in 293T cells. Recently, Naito et al. reported that c-FLIPL, but not c-FLIPS, promotes intracellular Wnt signaling in 293T cells by inducing the stabilization of ß-catenin through inhibiting the ubiquitylation of ß-catenin (35). We therefore compared the Wnt signal-enhancing activities of v-FLIP E8 and c-FLIPL in 293T cells. As recently reported, Wnt signaling was evoked by overexpression of c-FLIPL alone, regardless of Wnt3a stimulation, whereas E8 strengthened Wnt signaling only when cells were stimulated with Wnt3a, with the effect occurring in a dose-dependent manner (Fig. 4). c-FLIPL activates TCF-associated transcription in the absence of Wnt, while E8 enhances Wnt-induced signaling. In addition, coexpression of c-FLIPL and E8 was shown to synergistically enhance Wnt signaling. Putting these results together, it appears that c-FLIPL and E8 enhance the same Wnt canonical signaling pathway, but E8 and c-FLIPL enhance Wnt signaling downstream and mainly upstream, respectively, of stabilized ß-catenin.
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DISCUSSION |
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Human Kaposi's sarcoma-associated herpesvirus-encoded v-FLIP K13 did not show an enhancement of Wnt3a-induced signaling similar to that of E8 (Fig. 1C). Since its expression was much less than that of E8 (Fig. 1D), K13 may have the potential to enhance Wnt signaling. However, molluscum contagiosum poxvirus-encoded MC159, which, similarly to E8 and K13, is composed of two tandemly repeated DEDs, did not enhance Wnt3a signaling (Fig. 1C). This result is consistent with the phenotype of Tg mice expressing MC159 in T cells. These mice show a drop in total thymocyte yield much smaller than that in E8 Tg mice (54). We speculate that MC159 might be unable to bind to a putative E8 target molecule that plays an essential role in E8-induced stimulation of Wnt signaling. This hypothesis is consistent with previously reported differences between MC159 and E8 in binding to other molecules containing DEDs (6, 18).
When v-FLIP functions as an inhibitor of Fas-mediated apoptosis, v-FLIP binds to FADD and/or caspase 8 by homophilic interaction through their DEDs (6, 18, 49). v-FLIP has been reported to prevent proximity-induced autoactivation of caspase 8 in the so-called DISC, which is constituted by at least Fas, FADD, and caspase 8, by inhibiting the recruitment of caspase 8 into the DISC (5). However, these interactions were unnecessary in E8's enhancement of Wnt3a signaling, because this enhancement was observed in both FADD-deficient and caspase 8-deficient MEF cells (Fig. 2B and Fig. S2 in the supplemental material). Consequently, we conclude that v-FLIP must enhance Wnt signaling by binding to molecules other than FADD or caspase 8, using its DED, since E8 contains only two DEDs which are known to interact homophilically with DEDs of other molecules. Therefore, E8 may stimulate Wnt3a-induced signaling by interacting with an unidentified DED-containing protein(s), and identification of the target molecule(s) of E8 will be of importance to clarify the molecular mechanism of the Wnt signal-enhancing activity of E8.
Our results suggest that E8 enhances Wnt3a-induced signaling promoted by the interaction between ß-catenin and TCF (Fig. 3A). Wnt signaling is considered to be transduced not only by the so-called canonical pathway, which is activated by stabilized ß-catenin, but also by a noncanonical pathway independent of ß-catenin, such as a Ca2+-dependent pathway (44). Although we cannot completely eliminate the possibility that pathways other than the canonical pathway are involved in E8-induced enhancement of Wnt signaling, it is assumed that E8 stimulates the Wnt canonical pathway, since E8 also enhanced the transcriptional activity of the complex of TCF and the mutant ß-catenin without stimulation by Wnt (Fig. 3C). In the Wnt canonical pathway, stabilized ß-catenin has been shown to migrate into the nucleus and then form complexes with TCF/LEF (4, 32, 53). We examined the interaction of E8 and ß-catenin or TCF using a coimmunoprecipitation assay in 293T cells overexpressing E8 and ß-catenin or TCF. To date, we have been unable to detect an association of E8 with either TCF or ß-catenin under conditions in which interaction between TCF and ß-catenin was detected (data not shown). Thus, E8 may perform a function on Wnt signaling downstream of the stabilization of ß-catenin, without directly binding to ß-catenin or TCF.
Recently, Naito et al. reported that c-FLIPL could mimic Wnt-induced signaling in 293T cells, in cooperation with FADD, by preventing ubiquitylation and the subsequent degradation of ß-catenin (35). Although we tried to confirm these results, we were unable to obtain the same results in various cell lines in which E8 enhancement of Wnt signaling was detected. However, we were able to detect c-FLIPL-directed mimicking of Wnt signaling activity only in 293T cells (Fig. 4). c-FLIPL was shown to activate the Wnt signal by itself, while E8 increased the intensity of Wnt signaling only following initial stimulation of the Wnt signal. Moreover, E8 was indicated not only to function downstream of stabilized ß-catenin but also to function independently of both FADD and caspase 8 (Fig. 2B and 3). Thus, E8 and c-FLIPL seem to exhibit different effects on Wnt signaling. We suppose, however, that c-FLIPL might also possess the same Wnt signaling-enhancing activity as E8 downstream of the stabilization of ß-catenin in various cells, in addition to the activity mimicking Wnt-induced signaling in 293T cells.
v-FLIP has been shown to be associated with tumorigenesis (11, 46), such as the development of Kaposi's sarcoma and primary effusion lymphoma, although its effect is regarded to be due to the activation of NF-B and to be restricted to K13. It has previously been reported that E8 is involved in neither cell proliferation nor tumorigenesis (46), and it has been thought to function only as an inhibitor of apoptosis. However, because E8 was shown to induce the expression of endogenous cyclin D1 through enhancing Wnt3a signaling, it is likely that E8 can promote cell proliferation, and we found additional functions of E8 as a potent effector of cell proliferation. While Wnt3a signaling appears to slightly enhance and suppress the growth of KB and BALB/3T3 cells, respectively (see Fig. S3A and B in the supplemental material), E8 markedly enhanced the response of these cells to Wnt3a in a colony formation assay (Fig. 5). In the presence of E8, Wnt3a induces the growth stimulation of KB cells but not of U2OS and FL cells, and Wnt3a induces dramatic growth suppression or cell death in BALB/3T3 and MEF cells. To show that these effects were completely dependent on Wnt signaling, we analyzed the effect of ICAT. Although the expression of ICAT alone enhanced the growth of both KB and BALB/3T3 cells in the absence of E8 and Wnt3a (Fig. 5D and F), we were also able to show that ICAT definitely inhibits E8's regulation of the growth of KB and BALB/3T3 cells through Wnt3a signaling. E8 inhibits the proliferation of BALB/3T3 and MEF cells but does not show such an inhibitory effect on U2OS, KB, and FL cells. The different effects on cell proliferation between these cells may depend on different features of the cells; U2OS, KB, and FL cells are transformed, while BALB/3T3 and MEF cells are essentially untransformed. From this perspective, the phenotype of E8 Tg mice, which show a severe drop in thymocyte yield, might be explained by Wnt-induced growth retardation or death induction in thymocytes in the presence of E8. In conclusion, this work provides the basis of a novel in vitro system to analyze Wnt signaling in tumorigenesis, as well as the induction of differentiation or cell death. We are now performing further studies (i) to elucidate the molecular mechanisms of the E8-induced enhancement of Wnt signaling by identifying the target molecule that directly binds to E8 and (ii) to determine the basis of the dramatic Wnt3a-induced effects on cell growth in the presence of E8.
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ACKNOWLEDGMENTS |
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This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of the Japanese Government. S. Nakagiri was supported by the 21st Century COE Program of the MEXT, awarded to the Graduate School of Biostudies and Institute for Virus Research, Kyoto University.
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FOOTNOTES |
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Supplemental material for this article may be found at http://mcb.asm.org/.
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