SAP is an adaptor molecule with one SH2 domain and it is expressed in activated T and NK cells, where it is required for the appropriate signaling from the SLAM family of surface receptors. Deleted or mutated SAP genes that encode functionally defective protein are associated with the X-linked lymphoproliferative disease (XLP). This primary immunodeficiency is characterized by extreme sensitivity to Epstein–Barr virus (EBV) infection, dysgammaglobulinemia and a high rate of lymphoma development. The vigorous T- and B-cell proliferation that follows EBV infection and the high incidence of lymphomas (30%) in XLP patients might reflect functional defects in cell cycle and/ or apoptosis control. Our experiments show that SAP is a target of p53. In Burkitt lymphoma (BL) lines transfected with a temperatur-sensitive (ts) p53, SAP mRNA and protein expression was dependent on wild-type (wt) p53. Activation of endogenous wt p53 in BLs and lymphoblastoid cell lines led to the induction of SAP and this was inhibited by the specific p53 inhibitor pifithrin-α. Cell lines that carried mutant p53 did not express SAP under similar conditions. Moreover, we have shown binding of wt p53 to the promoter region of SAP by ChIP assay. Our results suggest that SAP contributes to the execution of some p53 functions.
The rare X-linked lymphoproliferative disease (XLP) usually presents only after Epstein–Barr virus (EBV) infection. The responsible gene has been identified by three different groups (Coffey et al., 1998; Nichols et al., 1998; Sayos et al., 1998) and it is called SAP/SH2D1A/DSHP. It encodes a short protein (128 aa) consisting almost entirely of one SH2 domain. SAP binds to molecules that belong to the immunoglobulin gene superfamily: SLAM, 2B4, NTB-A, Ly9, CD84. Initially, its function was thought to be masking of specific phosphotyrosine motives (Thr-Ile-pTyr-x-x-Val/Ile) in the signal transduction pathways. This was indicated by the demonstration that SAP inhibits the binding of SHP-2 to SLAM (Sayos et al., 1998; Shlapatska et al., 2001). Later, it was shown that SAP couples FytT to SLAM (Chan et al., 2003; Latour et al., 2003) and the surface–surface interaction between SAP and FynT does not involve the standard SH2 or SH3 binding.
In spite of the recent advances in identifying the SAP gene and determining some functions of the SAP protein, its role in the pathogenesis of XLP is not understood.
EBV-induced fatal infectious mononucleosis (IM) is the most important characteristic of XLP that manifests as uncontrolled T- and B-cell proliferation. It occurs in 50% of the affected individuals. Dysgammaglobulinemia and malignant lymphoma appear among the survivors of IM (in about 30% each), leading to the death of the patients by the age of 40 years. The malignancies are mostly non-Hodgkin B-cell lymphomas, but rare cases of Hodgkin lymphomas and T-cell lymphomas have also been described. It is estimated that XLP patients have a 200 times higher risk for lymphoma development than the general population (Grierson and Purtilo, 1987). In our present work, we focused our attention on the very high frequency of lymphomas. In view of the fact that the EBV-specific T-cell responses are impaired in XLP patients (Harada et al., 1982), it has been assumed that EBV contributes to the development of the lymphomas. However, only two EBV genome-positive lymphomas were documented (Harrington et al., 1987; Williams et al., 1993), and lymphomas appear in EBV seronegative XLP patients as well (Seemayer et al., 1995; Strahm et al., 2000; Sumegi et al., 2000). We have, therefore, searched for EBV-independent mechanisms that may be responsible or contribute to lymphoma induction. While the high lymphoma incidence might be, at least in part, a consequence of immunodeficiency, a defective control of cell cycle/DNA repair/apoptosis machinery may contribute as well.
Since p53 plays a key role in the control of cell proliferation and apoptosis and p53 knockout mice show a high incidence of lymphoid malignancies, we investigated whether SAP is part of the p53 network. We used the mutant p53 carrying EBV-negative, SAP-negative Burkitt lymphoma (BL) line, BL41, that has been transfected with a temperature-sensitive (ts) p53 mutant Val135 (Michalovitz et al., 1990). We found in this system that SAP was induced by wild-type (wt) p53 and this regulation occurred at the mRNA level. Furthermore, experiments with BL lines showed that the wt but not the mutant p53-carrying cells expressed SAP upon γ-irradiation. Similarly, in the wt p53 carrying BL2 line, DNA damage inflicted by cisplatin treatment induced SAP mRNA and protein and these were abolished by the p53 inhibitor pifithrin-α (PFT-α). In addition, we have demonstrated the binding of p53 to the promoter region of SAP gene, showing that SAP is a target of p53.
SAP protein is expressed in ts p53 carrying BL41 cells after induction of wt p53 conformation
Originally, BL41 cells carry a mutant p53. We used its subline transfected with a ts p53 that acts as a mutant protein at 37°C, but as a wt p53 protein at 32°C. By temperature shift, apoptosis occurred and p21 protein upregulated in accordance with published data (Ramqvist et al., 1993). At 37°C, the cells did not express SAP protein, but when cultured at 32°C, SAP was detectable after 24 h, its amount increasing further after 43 h (Figure 1a). The original, mutant p53-carrying BL41 line did not express SAP at 32°C (not shown). These results suggested that wt p53 induced SAP expression.
Next, we used the LMP1-transfected subline of the BL41 ts p53. When cells are cultured at 32°C, they arrest in G1 (p21 is induced), but they do not enter apoptosis because LMP1 (a protein encoded by EBV) upregulates bcl-2 (Okan et al., 1995). BL41 ts p53-LMP1 cells did not express SAP at 37°C, but became SAP positive after being in culture at 32°C for 1 day (Figure 1b). Since these cells do not die, they could be observed for longer time. The level of SAP increased after 2 or 5 days culture at 32°C (Figure 1b). Cells kept at 32°C could be rescued from the growth arrest by changing the temperature back to 37°C. At this temperature (37°C), the SAP level declined within 1 day, and completely disappeared after 2 days (Figure 1c), similar to the p21 expression (not shown). These experiments have proven that the induction of SAP protein is not merely a consequence of apoptosis, but requires activation of wt p53. Notably, the kinetics of SAP induction in BL41 ts p53-LMP1 cells was slower. This was in line with our previous finding showing that LMP1 downregulates expression of SAP (Nagy et al., 2002).
Since in the BL41 ts p53-LMP1 cells, the temperature shift leads to growth arrest, we tested whether expression of SAP is a consequence of growth arrest. We cultured BL41 and BL41 ts p53-LMP1 cells (at 37°C) in the presence of mimosine, a treatment known to induce p21 and growth arrest independently of p53. The growth of both cell lines was arrested, as indicated by the inhibition of [3H]thymidine incorporation (Figure 1d, upper panel), but they did not express SAP (Figure 1d, lower panel), demonstrating that growth arrest per se does not lead to SAP expression.
Wt p53 induced SAP mRNA
These results showed that activation of wt p53 in the BL41 cells is both necessary and sufficient for SAP expression. In order to test at which level SAP expression is regulated by p53, both cell lines (BL41 ts p53 and BL41 ts p53-LMP1) were cultured at 32°C and analysed for SAP mRNA. Cells expressing p53 with the mutant conformation were negative, whereas wt p53 induced the transcript in both cell lines (Figure 2a and not shown) as detected by RT–PCR. SAP transcripts were not detected in the parental BL41 cells cultured at 32°C (Figure 2a).
We also tested the kinetics of mRNA induction in BL41 ts p53-LMP1 cells cultured at 32°C by Northern blot analysis. SAP transcripts were detectable 8 h after temperature shift. This induction was independent of protein synthesis since it took place even in samples treated with CHX prior the temperature shift (Figure 2b). These results suggested that SAP is a direct target of p53.
SAP is induced by DNA damage in BL lines carrying wt p53
In order to test whether the activation of endogenous wt p53 has the same effect, DNA damage was induced by γ-irradiation in BL lines that carry wt p53 or mutant p53. Only EBV-negative BL lines were used because as we have shown, the EBV-positive type I BL lines express endogenous SAP (Nagy et al., 2002) where SAP is probably induced by EBV. The BL cells were irradiated (1000 or 800 rad) and tested for p53 and SAP protein expression after 24 h. Basal levels of p53 were different (higher in cells with mutant p53) and their upregulation occurred at variable degree. There was a clear correlation between SAP induction and p53 status. BL2 and BL28 that carry wt p53 expressed SAP, whereas BL41, DG75, JD38, BL49 and Ramos that have mutant p53 remained SAP negative after irradiation (Figure 3a and not shown). Similarly, in the wt p53-carrying BL2 cells, cisplatin treatment induced SAP expression as well. In order to exclude the possibility that SAP was induced incidentally by other, p53-independent pathways, we used the recently identified chemical inhibitor of p53: PFT-α (PFT-α). Treatment with PFT-α of BL2 cells prior to cisplatin exposure inhibited the induction of SAP (Figure 3c). Thus, activation of endogenous wt p53 induces SAP protein expression.
We also confirmed the induction of SAP mRNA under these conditions. Irradiation of BL2 cells led to the upregulation of SAP mRNA, whereas the mutant p53-carrying DG75, JD38, BL49 and Ramos lines remained SAP negative (Figure 3b and not shown). Cisplatin treatment also induced SAP mRNA and this effect was inhibited by the p53 inhibitor PFT-α, further supporting the role of p53 in the induction of SAP (Figure 3d).
DNA damage in lymphoblastoid cell lines (LCL) led to SAP protein expression
In our previous experiments, we did not detect SAP protein in normal B cells, and with the exception of two known cases (Shlapatska et al., 2001) LCLs are SAP negative as well. Since LCLs usually carry wt p53, we subjected them to DNA damage. Irradiation or cisplatin treatment induced SAP in all three LCLs tested (LS, Nadia, B25) (Figure 4a and not shown). On the contrary, irradiation of Mutu III, an EBV-positive BL line that has drifted to an LCL-like phenotype, but carries mutant p53, did not induce SAP expression (Figure 4a). In addition, both irradiation and cisplatin treatment of the CESS line (an LCL that expresses SAP constitutively) led to the upregulation of SAP. Irradiation of LCLs upregulated SAP mRNA as judged by RT–PCR (Figure 4b and not shown). These results showed that wt p53 induces SAP in LCLs as well.
SAP is upregulated in irradiated PHA-activated T cells
Since we showed SAP induction upon activation of wt p53 in cell lines (BLs and LCLs), we tested whether DNA damage could lead to SAP expression in normal cells as well. We irradiated nonactivated and PHA-activated blood-derived T lymphocytes with 1000 rad. After 24 h, SAP protein was upregulated in the PHA-activated cells (Figure 5), confirming that wt p53 induces SAP in normal cells as well.
SAP is not induced by wt p53 in nonlymphoid cell lines
Even though expression of SAP has only been described in lymphocytes, we tested whether wt p53 would induce its transcription in nonlymphoid cells. Following irradiation of the wt p53 carrying breast carcinoma cell line MCF-7, the p53 and p21 levels were upregulated (Figure 6a and not shown), but SAP was not detected by western blot or by RT-PCR (Figure 6a and b). Similar results were obtained on the small-cell carcinoma line A549 (not shown). These results suggested a tissue-specific induction of SAP by p53.
SAP gene contains potential p53 responsive elements
Our data strongly suggested that SAP was a p53 target. Since it is well established that p53 protein activates its target genes by binding to specific DNA sequences, we have carried out a search for such sequences in the SAP gene. Using the published consensus sequence (Bourdon et al., 1997), we did a computer-assisted search and identified two potential p53 responsive elements (p53RE). One sequence is located in the SAP promoter between positions 37112 and 37161 (p53RE1), and one in the 5′UTR at position between 39092 and 39136 (p53RE2) (using the AL022718 sequence). The p53RE sequences are shown in Figure 7a.
P53 binds to the RE1 located in the SAP promoter region
In order to test the functional interaction between p53 and the potential p53REs in the SAP gene within the context of organized chromatin, we performed chromatin immunoprecipitation (ChIP) assays. We confirmed the binding of wt p53 to p53RE1. The p53RE1 co-precipitated with p53, but not the p53RE2 (Figure 7b) when we used the irradiated BL2 (wt p53). As a negative control, we used the irradiated BL41 (mut p53) cells in which there was no binding between the mut p53 and any of the p53REs in the SAP gene. The irrelevant Ab, specific for the SV40 large T antigen, did not co-precipitate the p53REs in either cell line. In addition, no fragments were amplified from the samples that were processed without Abs (Figure 7b). These results strongly suggest that wt p53 mediates its effects on SAP via the p53RE1 located in the promoter of the SAP gene.
Mutations of the SAP gene are associated with XLP, an X-linked immunodeficiency syndrome, characterized by exceptional vulnerability to EBV infection. SAP protein was first detected in activated T cells. Later, we and others (Nagy et al., 2000; Parolini et al., 2000) have detected SAP in activated NK cells and in T- and NK-derived leukemias. The high expression of SAP in immune effector cells is consistent with the fact that the loss or mutation of the protein in XLP patients is associated with the impairment of both T- and NK-cell functions.
Besides fatal IM that is the major manifestation of XLP, malignant lymphomas also occur (with a 200 times higher frequency than in the general population). Although EBV-specific CTL functions are impaired in XLP patients, there is no sufficient documentation that EBV is involved in the development of malignant lymphomas in a similar way as in other immunodeficiencies (e.g. post-transplant lymphoproliferative disease), and lymphomas can also develop in EBV-negative XLP individuals (Strahm et al., 2000; Sumegi et al., 2000). It is therefore possible that the consequences of SAP dysfunction are not limited to immunodeficiency, but may extend to the apoptotic/cell cycle control/DNA repair system. Therefore, we aimed to elucidate whether SAP expression might be linked to the p53 pathway.
Several results concur in indicating that this is the case. Using ts p53 transfected, mutant p53-carrying EBV-negative BL cells of the BL41 line (Ramqvist et al., 1993), we found that induction of wt p53 conformation by temperature shift (32°C) induced SAP expression in the originally SAP-negative BL41 line. Experiments using the LMP1-carrying subline of these cells and those where cell cycle arrest was induced in a p53-independent manner proved that wt p53 activation is needed for SAP induction.
Experiments involving the induction of DNA damage by γ-irrariation or cisplatin treatment in different cell lines (BLs, LCLs) showed that SAP induction was expressed on the activation of wt p53. SAP was expressed following DNA damage only in cells that carried wt p53 (BL2, BL28 and LCLs). Induction of SAP following cisplatin treatment could be inhibited by PFT-α, a chemical inhibitor of p53 (Komarov et al., 1999).
Using the published consensus sequence (Bourdon et al., 1997), we identified two potential p53 responsive elements in the SAP gene. In ChIP assay, we proved the binding of p53 in the context of the organized chromatin to the sequence located in the SAP promoter between positions 37112 and 37161 (p53RE1). Thus, SAP can be added to the list of p53-induced genes involved in immune responses. ICAM-1 (Gorgoulis et al., 2003) and IRF-5 (Mori et al., 2002) were reportedly induced by p53. In addition, p53 mRNA is stabilized in PHA-activated PBLs (Voelkerding et al., 1995). These results suggest a role of p53 in immune responses.
After their expansion during an immune response, the number of antigen-specific lymphocytes returns to the baseline level. This is secured by apoptosis and the cessation of proliferation. Few experiments were conducted in order to clarify whether p53 has any role in this regulatory process. Uninfected or LCMV-infected p53-null mice had only slightly elevated numbers of CD8+ and CD4+CD44high cells and apoptosis of activated T cells was only slightly reduced in p53 mutant mice. On the other hand, CTLs were more readily generated from p53-null than from wt mice, indicating that p53-null effector cells survive longer after chronic exposure to antigen (Zhou et al., 1999). These results suggest that p53, and possibly SAP induced by p53, has a role in T-cell homeostasis, and this is more pronounced when the presence of Ag is sustained as it is in primary EBV infection for example. This is in line with the uncontrolled T-cell proliferation occurring in fatal infectious mononucleosis of XLP patients. Involvement of SAP in the termination/control of T-cell responses is suggested by the elevated numbers of T cells in SAP-deficient mice infected with LCMV or with murine gammaherpesvirus-68 (Czar et al., 2001; Wu et al., 2001; Yin et al., 2003). The upregulated SAP expression in the late phases of T-cell activation (Nagy et al., 2000) also suggest a role of SAP in T-cell homeostasis.
P53 is regarded as the ‘guardian of the genome’. In cells with damaged DNA, p53 triggers cell cycle arrest and this provides time for DNA repair. If repair is not efficient, apoptosis is induced. This eliminates the risk for illegitimate replication of damaged DNA. It is possible that SAP is involved in DNA repair, as suggested by the findings of Sylla et al. (2000), that is, in vitro binding of SAP to Ku70, Ku86 and DNA-PK, three major components of the DNA double-stranded break repair machinery. If SAP participates in the growth arrest or in the repair process, its deletions or nonfunctional mutations in XLP patients may facilitate the development of genomic instability that could lead to a high incidence of lymphomas.
Malignant lymphoma is the only tumor type described in XLP patients. The failure of p53 to induce SAP in the breast carcinoma line MCF-7 suggests that the regulatory processes in which SAP participates are restricted to lymphoid cells. Tissue-specific induction of p53 target genes has been previously shown (Fei et al., 2002). Our result supports the fact that the absence of a functional SAP does not influence tumor incidence in nonlymphoid tissues.
Materials and methods
Cell lines and treatments
BL2, BL28, BL41, BL49, JD38, Ramos, DG75 are EBV-negative and SAP-negative BL lines. Rael is an EBV-positive type I BL line and it is SAP positive. BL2 and BL28 carry wt p53, but all the other BL lines are mutated in the p53 gene. BL41 ts p53 was generated from the BL41 line, in which the ts p53-Val135 has been transfected (Ramqvist et al., 1993). Ts p53 has a mutant conformation at 37°C, but acquires wt conformation at 32°C. BL41 ts p53-LMP1 is its derivate in which LMP1 was cotransfected (Okan et al., 1995). LS, Nadia, B25, CESS are EBV-transformed LCL. Mutu III carries mutant p53 and is a BL line with a type III EBV gene expression pattern. Jurkat is a T-cell leukemia line, while MCF-7 is a wt p53-carrying human breast carcinoma line.
Peripheral blood mononuclear cells (PBMC) were separated from healthy blood donors by Ficoll-Paque (Pharmacia, Uppsala, Sweden) separation. T cells were obtained by negative selection and were activated with 1 μg/ml PHA.
For induction of DNA damage, cells were irradiated (800 or 1000 rad) in a CIS IBL 637, or treated with 5 μ M cisplatin (Sigma) for 3 h, washed, resuspended in fresh medium and cultured. For inhibition of p53, prior to the cisplatin treatment, cells were incubated with 20 μ M PFT-α (Sigma) for 1 h. PFT-α was readded to the cultures after cisplatin was washed out.
Mimosine (Sigma) was added to cultures for 24 h in a final concentration of 0.5 mM. Growth arrest was monitored in 1 × 105 cells seeded as triplicates in 200 μl medium in 96-well plates. For the last 16 h, 1 μCi [3H]thymidine was added to each well. The cells were harvested on a glass fiber filter and radioactivity was measured in a liquid scintillation counter.
The cells were lysed in loading buffer and aliquots corresponding to 5 × 105 cells were loaded in each well. We used a rabbit anti-SAP antiserum (kind gift of J Sümegi) generated against a sequence located at the C-terminus of the SAP protein, outside the SH2 domain. We detected p53 with DO-7 antibody. As a control for equal amounts of protein loaded, we detected β-actin by mAb Clone AC-15 (Sigma). For positive control, Rael or Jurkat lysates corresponding to 2 × 105 cells were loaded. Immunoblotting has been carried out as described previously (Nagy et al., 2000).
Total RNA was isolated by Trizol (Invitrogen) reagent, and 5 μg was used for the generation of cDNA by Superscript II™ (Life Technologies, Roskilde, Denmark) according to the manufacturer's protocol in 20 μl volume. The PCR reactions were performed in Rapidcycler™ (Idahotech) capillary PCR machine in 10 μl volume. The amplification reactions contained 1 μl of cDNA template, 50 mM Tris pH 8.0, 500 μg/ml BSA, 3 mM MgCl2, 200 μ M dNTP, 0.5 μ M of GAPDH primers; (GPDH5; IndexTermACC ACA GTC CAT GCC ATC AC, GPDH3; IndexTermTCC ACC ACC CTG TTG CTG TA), 1 μ M of SAP primers (XL37RTU; IndexTermCGC AGT GGC TGT GTA TCA T, XL37RTL; IndexTermACT TCT AGC TGA GGA CTT CTT CTC) (Sumegi et al., 2000) and 0.4 U Platinum™ Taq polymerase (Life Technologies). After an initial 15 s denaturation at 94°C, the reactions were cycled 30 times for GAPDH and 35 times for SAP under the following conditions: 94°C 0 s, 55°C 0 s, 72°C 30 s. The PCR products were separated on a 2.5% agarose gel in 1 × TAE buffer in the presence of 10 μg/ml ethidium bromide.
Total RNA (60 μg) extracted by Trizol (Invitrogen) reagent was fractionated on 1.5% agarose formaldehyde gel and transferred to Hybond-N membranes (Amersham Biosciences). The probe was generated by RT–PCR and labelled by [α32P]dCTP using High Prime labelling kit (Roche). The membranes were hybridized overnight in Rapid-hyb buffer (Amersham Biosciences), and after washing exposed to Phosphorimager for 2 days.
The ChIP assay was performed according to the manufacturers’ recommendation (Upstate Biotechnology). In 5 × 106 control and irradiated cells (20 h after irradiation), DNA and proteins were crosslinked with 1% formaldehyde (added directly to the culture medium) for 10 min at 37°C. After lysis (in the presence of protease inhibitors), the samples were sonicated to yield 200–1000 bp DNA fragments. Following centrifugation, samples were diluted 10-fold in ChIP dilution buffer (16.7 mM Tris-Hcl, pH 8.1, 167 mM NaCl, 0.01% SDS, 1.1% Triton X-100, 1.2 mM EDTA). In total, 1% of the samples was kept for input DNA. To reduce nonspecific binding, the diluted samples were precleared with salmon sperm DNA/Protein A Agarose–50% slurry for 2 h at 4°C with agitation. After a brief centrifugation, p53 protein IP was carried out using 3 μg p53-specific monoclonal antibody (Ab-1, Oncogene, San Diego). As negative controls, IP was carried out with an unrelated antibody directed against SV40 T antigen (Pab 419, Oncogen, San Diego) or with no antibody. Following overnight incubation at 4°C, the immunocomplexes were collected with salmon sperm DNA/Protein A Agarose–50% slurry (75 μl/ sample) for 2 h. Beads were washed several times and bound DNA–p53 complexes were eluted. Reverse of the formaldehyde crosslinking was performed by adding NaCl in the eluates to a final concentration of 0.2 M and by heating them at 65°C for 6 h. DNA was recovered by phenol/chloroform extraction and ethanol precipitation in the presence of 20 μg glycogen. The PCR reactions were performed in Rapidcycler™ (Idahotech) capillary PCR machine in 10 μl volume with the following primers:
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We thank Janos Sumegi (Cincinnati Children's Hospital Medical Center, MLC, Cincinnati, Ohio), Wang Qian (Division of Virology, National Institute for Medical Research, London) and Klas G Wiman (CCK, Karolinska Institute, Stockholm) for helpful discussions. The work was supported by the Swedish Cancer Society and by the Cancer Research Institute (New York)/Concern Foundation (Los Angeles).
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Nagy, N., Takahara, M., Nishikawa, J. et al. Wild-type p53 activates SAP expression in lymphoid cells. Oncogene 23, 8563–8570 (2004). https://doi.org/10.1038/sj.onc.1207908
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