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Correspondence to Philippe Pierre: pierre{at}ciml.univ-mrs.fr
In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation (maturation) that exhibits specific mechanisms to control antigen processing and presentation. Here, we show that in response to lipopolysaccharides, protein synthesis is rapidly enhanced in DCs. This enhancement occurs via a PI3K-dependent signaling pathway and is key for DC activation. In addition, we show that later on, in a manner similar to viral or apoptotic stress, DC activation leads to the phosphorylation and proteolysis of important translation initiation factors, thus inhibiting cap-dependent translation. This inhibition correlates with major changes in the origin of the peptides presented by MHC class I and the ability of mature DCs to prevent cell death. Our observations have important implications in linking translation regulation with DC function and survival during the immune response.
Abbreviations used in this paper: CHX, cycloheximide; DALIS, dendritic cell aggresome-like induced structures; DC, dendritic cell; iDC, immature DC; IRES, internal ribosome entry site; LPS, lipopolysaccharide; mDC, maturing DC; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3-kinase; TRIF, Toll-IL-1 receptor domain-containing adaptor-inducing IFN-β.
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B activation. DC activation results therefore in the enhanced ability to stimulate and polarize T cells in vitro and in vivo. A large proportion of newly synthesized proteins termed DRiPs are abnormal and degraded rapidly, thus contributing importantly to the MHC class I restricted endogenous antigenic peptide pool (Princiotta et al., 2003). Upon activation, DCs store ubiquitinated DRiPs in cytosolic bodies called dendritic cell aggresome-like induced structures (DALIS) (Lelouard et al., 2002). Ubiquitinated DRiPs storage in DALIS delays their processing and could contribute to regulate MHC class I presentation (Herter et al., 2005; Pierre, 2005). DRiPs and DALIS formation are tightly linked to protein synthesis and quality control (Lelouard et al., 2004). Through this study we explore different aspects of mRNA translation regulation and its consequences for DC function.
Protein synthesis regulation can be achieved through phosphorylation, inhibition, and proteolysis of key translation factors (Gingras et al., 1999). Extracellular stimuli such as growth factors activate translation through phosphoinositide 3-kinase (PI3K) and Ras signaling pathways. In contrast, viruses and cellular stresses inhibit translation through the phosphorylation and/or proteolytic cleavage of initiation factors such as eIF2
and eIF4GI (Holcik and Sonenberg, 2005). In addition to a general decline in protein synthesis, these events allow the translation of specific viral- or stress-related mRNAs. These mRNAs bear a complex structural element called internal ribosome entry site (IRES) that can directly recruit ribosomes under stress conditions and bypass the need for a 7mGpppN cap, which is normally recognized by the translation initiation complex. Thus, cap-dependent and cap-independent translations are most often regulated in opposite ways, IRES-mediated translation being relatively inefficient under physiological conditions.
We demonstrate here that LPS stimulation has a profound effect on the intensity and quality of translation in DCs both in vitro and in vivo. Translation control is tightly coordinated with the state of DC activation and can act independently of transcription regulation. LPS-stimulated bone marrow–derived DCs first undergo a phase of rapid up-regulation of protein synthesis. We show that this translational activation mediated by the PI3K/AKT signal transduction pathway is necessary for cytokine production, costimulatory molecules, and MHC class II surface up-regulation, as well as for DALIS formation in the first hours of LPS stimulation. At later stages of maturation eIF2 phosphorylation together with an increased production and degradation of eIF4GI and the eIF4GI-like factor DAP5, are correlated with the inhibition of cap-dependent translation and an increased resistance to apoptosis of mature DCs. Inhibition of cap-dependent translation also has an impact on MHC class I restricted antigen presentation, which at late time of DC maturation loses its dependence on protein neo-synthesis. Thus, translation regulation in response to LPS is required for proper DC function and survival.
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Up-regulation of maturation markers and DALIS formation are linked to PI3K signaling and translation activation
DC activation is phenotypically characterized by the surface up-regulation of MHC and costimulatory molecules, which are required for efficient antigen presentation and T cell activation. MHC class II molecule redistribution from the lysosomes of iDC to the cell surface of mDC is a key event in this process (Pierre et al., 1997). However, the respective contribution of preexisting and of newly synthesized molecules to this surface appearance is still debated. As translation is rapidly enhanced in response to LPS, we investigated the importance of PI3K signaling and protein synthesis in surface appearance of classical maturation markers such as CD86, MHC class II, and the production of IL-12, a key cytokine for DC function and T cell differentiation. LY treatment abrogated the surface appearance of the different markers and the production of IL-12, as illustrated by FACS staining of CD11c+ DCs activated with LPS (Fig. 3 A).
Thus, PI3K activity is absolutely required for functional LPS activation of DCs. Based on our observation that LY has a potent inhibitory effect on protein synthesis in DCs, we next tested whether direct inhibition of protein synthesis with the translation inhibitor cycloheximide (CHX) could also negatively impact on DC maturation. Upon CHX addition, CD86 and MHC class II surface up-regulation as well as IL-12 production were fully inhibited after 3 h of treatment (Fig. 3 A). This further demonstrates that protein neo-synthesis is required to achieve proper DC activation.
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Translation inhibition correlates with eIF2 phosphorylation
Having demonstrated PI3K involvement in increasing translation in response to LPS, we next investigated by which molecular mechanism(s) translation down-regulation could be achieved and its consequences during late phase of DC maturation. Cap-mediated translation inhibition can be achieved through the regulation of translation initiation by phosphorylation or proteolysis of key translation factors (Gingras et al., 1999). Cell defense pathways take advantage of four different kinases (e.g., PKR) to regulate protein synthesis in response to different environmental stresses by phosphorylating the subunit of the translation initiation factor 2 (eIF2-) (Anderson and Kedersha, 2002; Gebauer and Hentze, 2004). Phosphorylated eIF2- acts as a dominant-negative molecule and blocks the initiation of cap-dependent protein synthesis in stressed cells by inhibiting Met-tRNA recruitment.
We monitored eIF2 phosphorylation levels by immunoblot in maturing DCs (Fig. 4 A).
eIF2 phosphorylation increased between 4 and 8 h of DC maturation, suggesting that a stress-like response is induced by LPS. However, eIF2 phosphorylation in mDCs appeared limited when compared with control samples treated with arsenite (Fig. 4 A) in which translation was fully abrogated. Stress- or arsenite-induced eIF2 phosphorylation promotes the formation of stress granules (SGs), which serve as mRNA and preinitiation complex deposits until stress diminishes and protein synthesis can resume (Anderson and Kedersha, 2002). Thus, SG formation is a relatively good indicator of the eIF2 phosphorylation and associated translation inhibition levels. Immunofluorescence confocal microscopy was used to visualize SGs using a fluorescent oligo-dT probe in 16-h maturing DCs (Fig. 4 B). In absence of arsenite treatment, SGs were never observed during DC maturation, further supporting that the increase in eIF2 phosphorylation in maturing DCs is truly modest. Thus, in response to LPS, limited phosphorylation of eIF2 may modulate mRNA translation quantity and quality (Morley et al., 2005), although it is unlikely solely responsible for the dramatic translation inhibition observed during DC maturation.
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-C-FAG) (Cowan and Morley, 2004). Surprisingly, between 8 and 14 h of LPS activation, a time at which cap-dependent translation is down-regulated, eIF4GI levels increased sturdily (Fig. 5 B). In contrast, the levels of the closely related homologue eIF4GII and of eIF4A remained stable. The specific up-regulation of eIF4GI does probably not reflect a slower degradation rate because several smaller fragments weakly present in iDCs also increased after 8 h of LPS treatment. Interestingly, eIF4GI translation is enhanced in a context of general cap-dependent translation inhibition.
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The first cleavage site is positioned after the PABP-binding site and when cleaved, separates the N terminus of eIF4GI (e.g., NFc4) recognized by antibodies such as -Nt and -PABPd from the rest of the molecule. The second region is located after the eIF4E-binding site, thus allowing the production of fragments only recognized by -P7 and -P8 and containing the cap-binding protein eIF4E interaction domain (e.g., MF4 and MF5). The last cleavage domain was mapped in the vicinity, but distinct of the last known caspase-3 cleavage site, and produces fragments recognized by -P9, -phospho-S1149, and -C-FAG. The smaller eIF4GI fragments (e.g., MF4 and MF5), although containing the eIF4E binding site, were found to have a low affinity for eIF4E because they were not retained efficiently on a 7mG-cap affinity column (Fig. S2 B). Conversely, higher molecular weight eIF4GI fragments (>100 kD), possessing several other binding domains, were efficiently retained on the column and could therefore compete in the cell with intact eIF4GI for the recruitment of the cap-binding protein eIF4E and associated mRNAs. Thus, these fragments are likely to participate to the down-regulation of cap-dependent translation occurring during DC activation.
Identification of the proteolytic activity responsible for eIF4GI cleavage
In addition to caspase-3 and viral proteases known to degrade eIF4GI, the caspase-like activity of the proteasome has been shown in vitro to cleave eIF4GI in multiple fragments (Baugh and Pilipenko, 2004). To identify the protease(s) responsible for eIF4GI fragmentation, we used a panel of specific proteasome and caspase inhibitors and performed an immunoblot on mDCs (Fig. 5 D). The lack of inhibitory effect observed in the presence of the caspase-3 inhibitor DEVD-FMK confirmed that this caspase is not involved in eIF4GI cleavage in mDCs. Although none of the other specific caspase inhibitors tested had any inhibitory activity, the pan-caspase inhibitor Z-VAD-FMK prevented the accumulation of eIF4GI fragments. The same effect was observed with the reversible proteasome inhibitor MG132. Thus, the caspase-like activity of proteasome is likely to mediate at least partially the degradation of eIF4GI and play an active role in inhibiting translation in mature DCs.
Consequences of eIF4GI cleavage: IRES-mediated translation activation
In addition of being partly responsible for cap-mediated translation inhibition in mature DCs, we wondered if eIF4GI cleavage could have other functional consequences in DCs. Indeed, the major 50- to 65-kD fragments of eIF4GI (MF1 and MF2) are predicted to contain the first RNA-helicase eIF4A and the ribosome adaptor eIF3 binding domains, and are therefore equivalent to the eIF4GI fragments generated by different retroviral proteases (Alvarez et al., 2003). These fragments, as well as those generated by apoptosis or cellular stress induction, are known to act as IRES-transacting factors (ITAFs) and are central in switching from m7G cap-dependent to IRES-mediated translation during viral infection or cellular stress (Holcik and Sonenberg, 2005; Spriggs et al., 2005). In addition to viral mRNAs, they have been shown to induce protein synthesis from the cellular mRNAs of the pro-apoptotic factor APAF1 and of the eIF4GI family member DAP5 (Fig. 6 A) (Nevins et al., 2003). We thus investigated whether APAF1 and DAP5 expression levels were modified during DC maturation by immunoblot (Fig. 6 B).
APAF1 expression showed no significant variations upon DC maturation, whereas DAP5 expression was increased from 8 h of LPS activation. To examine whether the up-regulation of DAP5 could be due to transcriptional activation, quantitative PCR was performed (Fig. 6 C). DAP5 and APAF1 mRNAs were not induced more than twofold, DAP5 mRNA returning to basal levels after 8 h. Thus, mRNA transcription is not linearly correlated with the level of protein accumulation.
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Loss of eIF4GI and DAP5 up-regulation upon inhibition of their degradation
In addition of inhibiting cap-mediated translation, the proteolytic cleavage of eIF4GI and/or DAP5 during maturation is likely to control their own expression at the translational level. Thus, conversely to a classical situation in which inhibiting the degradation of a given protein increases its total level, interfering with eIF4GI cleavage should prevent the maturation-induced up-regulation of eIF4GI and DAP5. In agreement with this hypothesis, when mDCs were treated with MG132, levels of eIF4GI and DAP5 were drastically reduced in a dose-dependent manner (Fig. 7 A).
In contrast to MG132, LHVS, a general inhibitor of cysteine proteases, had no effect on the translation factors levels. Importantly, protein synthesis inhibition with CHX also reduced eIF4GI and DAP5 levels, thus confirming the importance of active translation to maintain steady-state levels of these molecules. To avoid potential indirect effect of MG132, the same experiment was conducted using Z-VAD-FMK to inhibit eIF4GI cleavage. A similar loss of eIF4GI and DAP5 was observed (Fig. 7 B). Thus, a strong link between proteolytic cleavage and increased production of the two translation factors exist in mDCs. Collectively, our results suggest that DC maturation promotes cleavage of eIF4GI and DAP5 into their potential ITAF fragments, thus boosting their own synthesis by favoring IRES-driven mRNA translation, in a global context of cap-mediated translation repression. Illustrating this conclusion and conversely to what occurred in mDCs, levels of eIF4GI and DAP5 increased upon MG132 or Z-VAD-FMK treatment in iDCs (Fig. 7 C). eIF4GI cleavage is therefore only functionally important in mature DCs.
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CD11c+ DC resistance to cell death was quantified by monitoring annexin V surface staining after treatment with MG132 or the pro-apoptotic drugs etoposide and staurosporine (Fig. 8 A). Although little LPS-induced death was observed, staurosporine treatment induced a strong annexin V labeling in 25% of the iDCs, whereas etoposide had a lesser effect. In contrast to iDCs, mDCs were not affected by the pro-apoptotic drugs, thus suggesting that maturation enhances their resistance to induced cell death. The contribution of eIF4GI and DAP5 proteolytic cleavage to this enhanced survival capacity of mDCs was evaluated using Z-VAD-FMK and MG132 at different doses (Fig. 8 A). Although MG132 treatment induced only a modest increase of cell death in iDCs, mDCs were extremely sensitive to the drug treatment. Most strikingly Z-VAD-FMK had no effect on iDCs even at higher doses (80 µM), while it efficiently promoted cell death in mDCs after a dose-dependent response in good correlation with the prevention of eIF4GI and DAP5 cleavage. Collectively, these results suggest that one of the functions of eIF4GI and DAP5 cleavage and translation inhibition in maturing DCs is to promote their survival, which otherwise might be affected by LPS stimulation.
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Detection of LPS by TLR4 activates PI3K through the recruitment of the MyD88 and TRIF adaptors, leading to AKT and mTOR activation and finally ending by S6 protein phosphorylation by S6K1. This signal transduction pathway is also activated by growth factors in replicating cells. TLR signaling is therefore likely to control the cellular metabolism, in addition to its stimulating role on immunity. It is a puzzling observation because mDCs are not dividing and therefore do not need a high rate of protein synthesis to sustain proliferation. Putatively, a high rate of translation is required for achieving the massive cellular changes observed upon DC maturation such as MHC and costimulatory molecules up-regulation, as well as cytokine production. Interestingly, our observation that IL-12 secretion is prevented during PI3K inhibition by LY contrasts with previous results obtained by Fukao et al. (Fukao et al., 2002), in which DC treatment with wortmannin was found to enhance IL-12 production. We attribute this discrepancy to the use of wortmannin, which, at the concentration used, is less efficient than LY to inhibit PI3K in DCs (as shown in Fig. 2 B). Partial inhibition of the PI3K pathway could lead to potential compensation mechanisms able to promote IL-12 production.
The abrupt increase in protein synthesis is also likely to enhance markedly the proportion of DRiPs available for processing. In this context, DALIS probably represent an adapted stress response to these radical changes in protein synthesis and to the massive accumulation of DRiPs in such a short time lapse. DALIS are dependent on the signaling pathway inducing the translational boost, comprising the PI3K/AKT/mTOR signaling axis, which is key to achieve functional DC maturation. DALIS formation and disappearance follow the enhancement and inhibition of cap-mediated translation during DC maturation. By accumulating DRiPs, DALIS provide probably a mean to control the cytotoxic effects of these misfolded proteins, as well as their availability for degradation. Surprisingly, although the rate of surface arrival of peptide-loaded MHC class I does not fluctuate with maturation progression, the type of antigen presented changes dramatically. From fully dependent on newly synthesized antigens at early time of maturation, in agreement with the DRiPs hypothesis, MHC class I presentation switches to a pool of preexisting antigens at late stages of maturation. Thus, these antigens could be provided by decaying DALIS or alternatively they could be of exogenous origin and mostly cross-presented. In absence of a mean to control DALIS formation efficiently without affecting DC maturation, the elucidation of their exact function will remain unanswered. However, we could demonstrate that translation regulation affects the pool of antigen available for MHC class I presentation and that MHC class I restricted presentation is radically different in cells stimulated with LPS for different times.
A reduction in cap-dependent translation and a shift toward translation of certain IRES-containing mRNAs was observed after 8 h of maturation. Remarkably, this process is similar to the stress-induced attenuation of protein synthesis required for cell survival under harsh conditions. In addition to a mild phosphorylation of eIF2, we observed a good correlation between eIF4GI and DAP5 proteolysis and the intensity of their translation during maturation. Moreover, protease inhibitors preventing eIF4GI and DAP5 cleavage had a strong inhibitory effect on the production of these molecules in a manner similar to protein synthesis inhibitors, thus definitely linking proteolysis and translation regulation. We could show that the protease(s) responsible for the cleavage of eIF4GI are different from the major known apoptotic caspases, such as caspase-3, which is responsible for translation inhibition during apoptosis. Based on MG132 effects and on a recent report (Baugh and Pilipenko, 2004), we further propose that proteasome activity could be responsible, at least in part, for the degradation of the translation initiation factors and, thus, exert a control on translation in mDCs. Interestingly, MG132 treatment is known to affect viral IRES activity (Baugh and Pilipenko, 2004) as well as to induce translation reprogramming of myoblasts (Cowan and Morley, 2004). The effect observed with the broad range inhibitor of caspases Z-VAD-FMK could be due either by inhibition of an additional unidentified protease or by inhibition of the caspase-like activity of the proteasome itself because a survey of eIF4GI primary sequence for sites potentially targeted by the proteasome caspase-like activity (Kisselev et al., 2003) indicates the presence of several consensus sites in areas matching eIF4GI cleavage map.
Cell death appears to be a normal response to counter-balance the activation of the proliferation machinery (including protein synthesis enhancement). The establishment of anti-apoptotic conditions during DC maturation seems dependent, at least in part, on the switch in the quality of translation induced by proteolytic cleavage of eIF4GI and DAP5. LPS detection by DCs is therefore integrated in a binary response containing a growth factor-like and a stress-like phase. This response is adapted to the need for rapid changes in the physiology of DCs after pathogen detection. Marked up-regulation of protein synthesis probably favors apoptosis through the accumulation of misfolded proteins. DCs therefore take advantage of the second phase to enhance their survival rate and augment their capacity to interact with other cells during their migration. Whether this phase is directly triggered by LPS or indirectly by an autocrine cytokine loop remains to be evaluated. IL-6 could cause some of these changes because it has been shown to favor some IRES-mediated translation (Yamagiwa et al., 2004).
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Chemicals
All chemicals were purchased from Sigma-Aldrich, except Z-VAD-FMK, Z-DEVD-FMK, Ac-YVAD-CMK, and Ac-LEHD-FMK (from Bachem); Z-IETD-FMK, Z-WEHD-FMK, rapamycin, and LY294002 (from Calbiochem); and MG132 (from BIOMOL International, L.P.). iDCs were treated with 100 µM LY294002 or 1 mM rapamycin for 1 h before LPS treatment. Wortmannin was used at 1 µM for 30 min before activation. 0.5 mM sodium arsenite was added for 30 min to iDCs or to 16 h LPS-treated DCs. 10–80 µM Z-VAD-FMK; 0.5–2 µM MG132; 2 µM LHVS (gift of H. Ploegh, Massachusetts Institute of Technology, Cambridge, MA); 100 µM Z-DEVD-FMK, Ac-YVAD-CMK, Ac-LEHD-FMK; 40 µM Z-IETD-FMK, Z-WEHD-FMK; 25 µM CHX; 50 µM etoposide; or 0.2–1 µM staurosporin was added for 10 h to iDC or to 6 h LPS-treated DC.
Immunoblotting
50 µg of Triton X-100–soluble material was loaded on 2–12% gradient SDS-PAGE before immunoblotting and chemiluminescence detection (Pierce Chemical Co.). Polyclonal antibodies against eIF4A, Nt eIF4GI, and Nt DAP5 were from Santa Cruz Biotechnology, Inc.; polyclonal antibodies against phospho-S6, phospho-S6K1, S6, phospho-AKT, eIF2, and Ct DAP5 were from Cell Signaling Technology; polyclonal antibody against phospho-eIF2 was from Invitrogen. Polyclonal antibodies specific for eIF4GI peptides P7, P8, and P9 were a gift of R. Rhoads (Louisiana State University, Baton Rouge, LA). Others polyclonal antibodies specific for eIF4GI and eIF4GII were gifts of S.J. Morley (University of Sussex, Brighton, UK). Secondary antibodies were from Jackson ImmunoResearch Laboratories and from Invitrogen. Immunofluorescence and confocal microscopy was performed with a microscope (LSM 510; Carl Zeiss, Inc.) using a 63x objective and accompanying imaging software.
MHC class I surface recovery by acid striping assay
5 x 106 cells were washed in PBS/0.1%BSA and resuspended in 0.5 ml of 0.2 M citric acid/0.2 M Na2HPO4 buffer (pH 3.0) and incubated on ice for 2 min. The cell suspension was neutralized by adding excess of ice-cold PBS/BSA and after centrifugation cells were immediately stained for FACS analysis or for recovering resuspended in LPS-free medium with or without drugs. Cell surface Kb molecules were measured by FACS after staining with HB176 (gift of Günter Hämmerling and Franck Momburg, Heidelberg).
m7G-cap binding assay
500 µg of soluble fraction were diluted in 300 µl lysis buffer and incubated with 20 µl packed 7-Methyl GTP-Sepharose 4B (GE Healthcare) for 2 h at 4°C. After washing with lysis buffer, the beads were applied to SDS-PAGE and immunoblot was performed as above.
Plasmids and in vitro transcription
Constructs are in a pBluescript-KS (Stratagene) vector. Plasmids encoding firefly luciferase, pT3LUC(pA), was the gift of M. Hentze (EMBL, Heidelberg). 20 µg plasmid DNA were linearized and purified with the QIAquick PCR purification KIT (QIAGEN). 10 µl linearized DNA were in vitro transcribed in the presence of either 7mGpppG or ApppG (Ambion) using the Riboprobe in vitro Transcription System-T3 (Promega). In vitro transcribed mRNA was purified using the RNeasy Mini kit (QIAGEN).
mRNA transfection
iDCs were transfected on d 5 of culture. Before transfection, iDCs were washed twice with ice-cold PBS. DCs were then adjusted to a final cell density of 20 x 106 cells/ml. 200 µl of the cell suspension (4 x 106 cells) was preincubated in a 4-mm gap electroporation cuvette (Bio-Rad Laboratories) for 5 min on ice. In vitro–transcribed mRNA (5 µg) was added to the cell suspension and cells were pulsed with a Gene Pulser II apparatus (Bio-Rad Laboratories), using a voltage of 500 V, a capacitance of 50 µF, and pulse times ranging from 2 to 4 ms. After electroporation, cells were immediately resuspended in fresh prewarmed culture medium. After 4 h, cells were harvested and luciferase activity was determined with a Luciferase Reporter Assay System (Promega) in a Wallace 1420 multilabel counter VICTOR2.
Online supplemental material
Figures presenting the effect of MyD88 and TRIF deficiency on DC maturation, the cap-binding activity of eIF4GI fragments and DAP5 isoforms expression in DCs are displayed as supplementary figures.Online supplemental material is available at http://www.jcb.org/cgi/content/full/jcb.200707166/DC1.
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Acknowledgments |
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This work is supported by grants to PP from the Ministère de la Recherche et de la Technologie (ACI BCMS), La Ligue Nationale Contre le Cancer and the Human Frontier of Science Program. EKS is supported by the MRT. MC is supported by the Swiss National Research Fund. PP is part of the EMBO Young Investigator Program and of the DC-THERA FP6 NoE.
Submitted: 24 July 2007
Accepted: 26 November 2007
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