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Address correspondence to Alexandra Chittka at her present address, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Tel.: (44) 20-7679-3365. Fax: (44) 20-7679-2091. email: a.chittka{at}ich.ucl.ac.uk
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Abstract |
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Key Words: p75NTR; cell cycle; HDAC; transcriptional repressor; PR/SET domains
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Introduction |
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Neurotrophins, such as NGF, BDNF, and NT-3, are important survival and differentiation factors. The neurotrophins interact with two distinct classes of receptors, members of the Trk tyrosine kinase receptor subfamily and p75NTR, a member of the TNF receptor superfamily (Chao and Hempstead, 1995). There is evidence that p75NTR can function as a cell death receptor (Casaccia-Bonnefil et al., 1996; Frade et al., 1996; Bamji et al., 1998; Frade and Barde, 1998). Several proteins that interact with p75NTR have been shown to transduce apoptotic signaling. These include NRIF (Casademunt et al., 1999), NRAGE (Salehi et al., 2000), and NADE (Mukai et al., 2000). Interestingly, p75NTR is expressed very early during development (Yan and Johnson, 1987, 1988), before differentiation of many precursor cells of the nervous system and before the onset of programmed neuronal cell death. This observation makes it a candidate for a receptor functioning in the control of precursor cell proliferation and differentiation. Supporting this idea is the observation that several proteins which interact with p75NTR induce growth arrest. Expression of SC1, for example, was previously found to be correlated with a decrease in BrdU incorporation (Chittka and Chao, 1999).
To elucidate the mechanism by which SC1 transduces the neurotrophin signaling, we began to analyze its potential transcriptional activity. In a reporter gene assay, SC1 acted as a transcriptional repressor. Both the zinc finger domains as well as the PR/SET domain are necessary for SC1 to act as a repressor, and are needed to effectively block BrdU incorporation into cell nuclei. The repression exerted by SC1 required the activity of trichostatin A (TSA)sensitive histone deacetylases (HDACs), and SC1 was found in the complex with HDAC 1, 2, and 3. Further, we show that SC1 behaves as a transcriptional repressor upon NGF application to the cells transfected with both SC1 and either p75NTR or TrkA. We found the zinc finger domains of SC1 are necessary for its nuclear localization. Finally, our analysis of genes transcriptionally regulated by SC1 revealed that SC1 down-regulates the expression of a promitotic gene, cyclin E, consistent with its ability to block DNA replication as measured by BrdU incorporation. These results implicate SC1 as a potential transcriptional mediator of NGF signaling that may be involved in modifying the chromatin structure during differentiation.
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Results |
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To define the domains of SC1 responsible for the repressive activity, we created truncated fusion proteins of NH2-terminally Flag-tagged SC1 with the Gal4-DBD and used them for transfection of HEK293 cells in our reporter assays. Three truncated proteins were made: (1) 754-798 lacks the extreme COOH terminus, which contains a highly acidic domain; (2)
583-798 lacks the six zinc finger domains in addition to the COOH-terminal domain; and (3)
404-798 lacks the PR domain and the entire COOH terminus. (see Fig. 2 B for the schematic representation of the fusion proteins). Expression of these proteins was verified by transfection of HEK293 cells and subsequent immunoprecipitation of the proteins using anti-Flag antibodies (Fig. 2 C).
We observed that deletion of the zinc finger domains from SC1 leads to a loss of its repressive activity (Fig. 2 B, compare lane 583798 lacking the zinc fingers with Gal4 alone), whereas deletion of the acidic-rich COOH terminus had no influence on the repression by SC1 (Fig. 2 B, compare lane
754798 lacking the COOH-terminus with Gal4 alone). Interestingly, deletion of the PR domain rendered SC1 a transcriptional activator, as can be seen from an increase in luciferase activity over the control levels (Fig. 2 B, compare lane
404798 with Gal4). Such behavior has been observed for Blimp/PRDI-BF1 (Ren et al., 1999; Yu et al., 2000). We noticed that the truncations of the zinc fingers and the PR/SET domain led to a reduction of the total protein levels detected. To exclude the possibility that the increase in the luciferase activity observed upon the truncations of SC1 is due to the decrease of the protein level, we performed a series of experiments where an increasing amount of DNA encoding these proteins was transfected and luciferase measurement was performed. We obtained similar results in these experiments (Fig. 2 C, bottom graph).
As many transcriptional repressors recruit HDACs and need this activity to exert their repression (Grunstein, 1997; Pazin and Kadonaga, 1997; Wolffe, 1997), we tested whether TSA, a potent inhibitor of HDACs, influences the repressive activity of SC1 in the transcriptional reporter assays. Fig. 3 A shows that the repressive activity of SC1 was completely abolished by the addition of 50 ng/ml TSA, indicating that SC1's repression relies on the activity of TSA-sensitive HDACs. To directly test the interaction between SC1 and HDACs, we cotransfected Flag-tagged SC1 with HA-tagged HDAC 1, 2, or 3 into HEK293 cells and performed a coimmunoprecipitation assay. Anti-Flag Sepharose was used to bring down the Flag-tagged SC1. Expression of the fusion proteins was monitored by Western blot analysis. Cotransfection of Flag-vector with HDACs was used as a negative control. The results of these experiments are presented in Fig. 3 B, which demonstrated that SC1 can be found in a complex containing all the tested HDACs. Thus, SC1 associates with the class I HDACs and is likely to exert its repression by the recruitment of these proteins to the appropriate promoter sites.
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First, we determined the time course of expression of cyclins E, A, and B in these cultures by performing Northern blots at 0, 4, 8, 12, 16, 20, and 24 h after serum addition. Cyclin E could be detected at 12 h first and persisted until 24 h, cyclin A could first be detected at 20 h, and cyclin B was first detected at 24 h after serum addition of the growth-arrested cells (unpublished data). The cells were transfected with either SC1-bearing plasmid or a control plasmid, and lysates were collected at the following time points after serum addition: at 12 h for cyclin E measurement; at 20 h for cyclin A measurement; and at 24 h for cyclin B measurement. Subsequently, luciferase activity was measured in these lysates. We observed that cyclin E was down-regulated as measured by the luciferase activity, and the repression of the cyclin E promoter was comparable in magnitude to the repression exerted by SC1 when it is tethered to the Gal4 moiety (compare Fig. 7 A with Fig. 2 A). There was also a slight reduction of cyclin B expression as measured by the luciferase activity (Fig. 7 C). Expression of cyclin A, the major cyclin acting during S phase of the cell cycle, was not down-regulated by SC1 in these experiments (Fig. 7 B). To verify that the cyclin genes are expressed in these cells, we performed RT-PCR to monitor the endogenous expression of the cyclins (Fig. 7). Then, we investigated whether the levels of endogenous cyclin E protein were affected by the overexpression of SC1. To this end, we analyzed the protein lysates from NIH3T3 cells that had been transfected with either SC1 or a control Flag-bearing plasmid and treated as described above. Equal amounts of total protein were loaded on the gels, which were then transferred for Western blot analysis. We used an anti-cyclin E antibody to detect the levels of total cyclin E protein in these lysates, and normalized these by probing the blots with an anti-actin antibody (Fig. 7 D). The images were analyzed using a densitometer to determine the relative levels of cyclin E and actin present in transfected and mock-transfected cells, and were corrected for the transfection efficiency of these cells (which was routinely between 30 and 40%). We calculated a reduction of the total cyclin E protein level by a factor of 2.5 in cells overexpressing SC1, supporting our previous observations on the repression of the cyclin E promoter in the reporter assays (see Fig. 7 A).
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Discussion |
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Analysis of the transcriptional activity by SC1 revealed that it acts as a transcriptional repressor both in the context of being tethered to a DBD of another protein, Gal4, and by itself in transfection experiments. Our data indicate that the six zinc finger domains and the PR/SET domain are required for transcriptional repression by SC1. This implicates the zinc finger's and PR/SET domain's direct involvement in transcriptional activity either by allowing DNA binding of SC1 or by recruitment of other proteins that may modulate transcriptional repression. Consistent with the latter hypothesis, we observed that SC1 exerts its repressive activity by recruiting TSA-sensitive HDACs. Complexes involving HDACs have been implicated in silencing neuronal-specific genes (Naruse et al., 1999; Ballas et al., 2001). SC1 is an HDAC-dependent repressor, which may be involved in actively predisposing cells for differentiation by blocking their proliferative potential through down-regulation of promitotic genes.
Interestingly, truncation of the region of SC1 that contains the PR/SET domain transforms SC1 into a transcriptional activator, thus pointing to an involvement of this domain in repressive activity of SC1. Similar observations were made when Blimp-1's PR domain was removed (Yu et al., 2000). In this respect, it is noteworthy that two related proteins (RIZ and MDS1-EVI1) encode two different transcripts, which differ only in the presence of the PR/SET domain in the respective proteins (Bartholomew and Ihle, 1991; Liu et al., 1997). The absence of the PR/SET domain correlates with a weaker repressive activity in RIZ protein (Xie et al., 1997), suggesting a modulatory role of PR/SET domains during repression. Additionally, Blimp-1/PRDF-BF1 can exert repression through its PR/SET domain (Ghosh et al., 2001).
SET domains are found in chromosomal proteins that modulate gene expression and chromatin structure (for review see Jenuwein, 2001). Several proteins containing SET domains possess lysine histone methyltransferase activity (O'Carroll et al., 2000; Rea et al., 2000; Strahl et al., 2002). These histone modifications can lead to transcriptional repression (Firestein et al., 2000), but other enzymes are likely to be required, e.g., HDACs, to act together with methyltransferases. We do not know whether the PR/SET domain of SC1 possesses a protein methyltransferase activity. However, given SC1's ability to repress transcription in an HDAC-dependent manner, it would make SC1 a prime candidate for developmental regulation and subsequent maintenance of differentiation. Such a role is further substantiated by the observation that SC1's action is correlated with a block of BrdU incorporation, suggesting a role in cell differentiation and possible maintenance of the differentiated state.
One of the genes whose transcription is negatively regulated by SC1 is cyclin E, the major cyclin at G1S phase transition. The down-regulation of cyclin E is consistent with the hypothesis that SC1 may play a major role at the G1S decision making stage, and possibly during terminal mitosis as the cells prepare to enter a differentiative program. A down-regulation of cyclin E mRNA was observed by Tramtrack protein during glial development in Drosophila melanogaster, blocking entry into S phase and thus regulating glial cell proliferation (Badenhorst, 2001). Additionally, the activity of cyclin E together with CDK2, its binding partner, is instrumental for the regulation of cell cycle progression in neural and glial progenitor cells, and its block leads to an efficient cell cycle arrest (Casaccia-Bonnefil et al., 1999; Ferguson et al., 2000). Thus, SC1 may be one of the key regulators determining the decision of proliferating cells to exit cell cycle in the nervous system.
Several interesting points arise concerning the possible role of SC1 in neurotrophin signaling. It has been shown that in PC12 cells, the responsiveness to NGF is cell cycle stage-dependent (Rudkin et al., 1989), i.e., they will respond by differentiating when in G1 phase, but progress through the cell cycle when exposed to NGF during the other cell cycle phases (van Grunsven et al., 1996a, b). This responsive difference to NGF can be partially explained by the different temporal cell surface expression of TrkA and p75NTR (Urdiales et al., 1998). Thus, TrkA is observed on the cell surface during late M/early G1 phase, whereas p75NTR is highly expressed at the surface during the remaining time of cell cycle. Consistent with this temporal expression of the two NGF receptors, SC1 may act as a transducer of anti-proliferative signaling by NGF at an appropriate cell cycle stage, i.e., at G1S transition as a blocker of further S phase entry. We observed that both TrkA and p75NTR enhanced the repressive activity of SC1 in our cotransfection experiments, implying the role of SC1 as the transducer of NGF signaling by these two receptors. This observation is particularly interesting in view of our data, showing that NGF enhances the repressive activity of SC1 at the cyclin E promoter in PC12 cells. As such, SC1 could play a decisive role during the differentiation of PC12 cells upon NGF addition. Specifically, as the decision to exit the cell cycle is made during G1 phase in these cells and both TrkA and p75NTR are expressed at this stage, they would be involved in mediating the anti-mitogenic response through SC1 as one of the key players in this process. The observations presented here offer novel venues for probing the molecular mechanism of NGF action as it is transduced by both TrkA and p75NTR through the activation of SC1.
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Materials and methods |
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Plasmids
We used 0.75 µg 5xGal4 UAS-luciferase DNA (a gift of Al Fisher, Cornell University Medical College, New York, NY; Catron et al., 1995); 0.25 µg Gal4SC1 or other deletion mutants of SC1, and 0.05 µg pCMV-ßgal DNA for transfections of HEK293 cells. The same relative ratios and amounts of plasmid DNA were used for transfections with cyclin-specific luciferase constructs. Reporters were used as follows: pGL2-cyclin E-luc containing 1.4 kb of cyclin E promoter; pGL2-cyclin B-luc containing 3.8 kb of the cyclin B promoter; and pGL2-cyclin A-luc containing 3.5 kb of cyclin A promoter (all these were gifts of E. Kerkhoff, University of Würzburg). As an effector, pSC1 construct was used, which is an NH2-terminal fusion of full-length SC1 with a Flag tag (Chittka and Chao, 1999). GFP fusion proteins were generated as follows: full-length SC1, SC1
ZF (deletion from H608 to H744) and SC
C (deletion from K749 to the end of the protein) were subcloned into pEGFP-C3 (CLONTECH Laboratories, Inc.) using HindIII and BamHI restriction sites. SC1
ZF was created by generating an NdeI site in the full-length cDNA. Subsequent digestion with NdeI resulted in a construct without the zinc fingers. SC-1
PR was created by generating a PstI restriction site in the full-length cDNA. Digestion with PstI resulted in a construct without the PR domain. HA-tagged HDAC 1-, 2-, and 3-bearing plasmids were gifts of R. Evans (The Salk Institute for Biological Studies, La Jolla, CA). The TATA-luc plasmid was a gift of Heike Boemmel (University of Würzburg).
Immunocytochemistry
For the experiments using NIH3T3 and HEK293 cells, BrdU was purchased from Sigma-Aldrich and used according to a previously published protocol (Krek and DeCaprio, 1995). Cells were plated on sterile glass coverslips coated with poly-ornithine and were pulsed for 23 h with 10 µM BrdU before fixation with cold 50:50 methanol/acetone for 23 min. Immunostaining was performed as suggested by the manufacturer of the anti-BrdU antibody kit (Zymogen). Immunostaining of labeled cells with a monoclonal anti-FLAG FITC-conjugated antibody (Upstate Biotechnology) to visualize SC1-expressing cells was performed according to the manufacturer's instructions. Coverslips were embedded in Mowiol after washing. COS1 and Schwann cells were plated as above, except that poly-D-lysine was used for coating the coverslips. They were pulsed for 24 h with 10 µM BrdU before processing for immunocytochemistry. The cells were fixed in 4% PFA in PBS. Primary anti-BrdU antibody from DakoCytomation was used, with subsequent visualization by application of antimouse rhodamine-conjugated secondary antibody from Jackson ImmunoResearch Laboratories. Scans of stained cells were made using a confocal microscope (model TCS; Leica) for NIH3T3, COS1, and Schwann cells with identical settings for pinhole and voltage for any panel of analysis, and a fluorescent microscope (model IX70; Olympus) was used for HEK293 cells.
RT-PCR for cyclin-specific mRNA
RNA was extracted from the cells using TRIzol® (Invitrogen), according to the manufacturer's instructions. RT-PCR was performed using the SuperScriptTM II kit (Invitrogen). Primers were used as follows: cyclin E, forward: 5'-GTGAAAAGCGAGGATAGCAG-3', reverse: 5'-TGTTGTGATGCCATGTAACG-3'; cyclin B, forward: 5'-GGCACTGTTAAAGCCCTACC-3', reverse: 5'-GTTCTGCATGAACCATC-3'; and cyclin A, forward: 5'-AAGGACCTTCCTATAAAC-3', reverse: 5'-TTCTCCCACCTCAACCAG-3'. Cycling was performed as follows: for cyclin E and cyclin B: 5 min at 94°C for 1 cycle; 30 s at 94°C, 30 s at 53°C, 30 s at 72°C for 30 cycles; 10 min at 72°C for 1 cycle. For cyclin A, the annealing was performed at 50°C.
Co-immunoprecipitation experiments and Western blotting
Co-immunoprecipitations of Flag-SC1 and HDACs were performed as follows: HEK293 cells were transfected with either Flag-SC1 or Flag alone and HDAC 1, 2, or 3, and were harvested 48 h after transfection. Cells were lysed using RIPA buffer on ice and centrifuged to get rid of cell debris. Lysates were then precleared using protein A/G beads (Amersham Biosciences) and Flag-tagged proteins were precipitated using anti-Flag M2 Sepharose (Sigma-Aldrich). The beads were then washed with RIPA buffer 45 times and the immune complexes were separated by SDS-PAGE. Half of the reaction was run out on a 10% gel, blotted and probed for HDACs using anti-HA antibody (Santa Cruz Biotechnology, Inc.); another half was separated on a 7.5% gel, blotted and probed with anti-Flag M2 antibody (Sigma-Aldrich) to detect SC1. For Western blotting with anti-cyclin E antibody, we used a polyclonal antibody (Santa Cruz Biotechnology, Inc.); the anti-actin mouse monoclonal antibody was from DakoCytomation.
siRNA experiments
SC1 siRNA was obtained using the SilencerTM siRNA Cocktail Kit (RNase III; Ambion). As a template for the in vitro transcription, a fragment of 1.2 kb corresponding to nucleotides 11200 of the rat SC1 sequence was subcloned in pcDNA3 in both orientations. PC12 cells were transfected with SC1 siRNA or scrambled siRNA (0.5 µg/well) using LipofectAMINETM 2000. 24 h later, cells were serum starved for 24 h. Serum-containing medium was added, and 2448 h later, cells were collected directly in protein loading buffer and boiled for 5 min. Western blotting was performed to determine levels of SC1, cyclin E, cyclin A, and actin.
SC1 antibodies
Antibodies against SC1 were obtained from rabbits injected with the peptide GSMTTEGCRMSSAVYSADESLSAHKC coupled to KLH. Antibodies were purified using an affinity column with the peptide coupled to CNBr Sepharose (Roche). Antibodies were used at 2 µg/ml for Western blotting.
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft grants SFB487, TPC4, and SFB465, TPA3; J.C. Arevalo was supported by a postdoctoral fellowship from the Spanish Ministry of Education; M.V. Chao was supported by National Institutes of Health grant CA56490; and Pilar Pérez was supported by Junta de Castilla y León (CSI5/02).
Submitted: 24 January 2003
Accepted: 9 February 2004
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