1 Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA
2 Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France
Correspondence
John Brady
bradyj{at}exchange.nih.gov
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ABSTRACT |
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INTRODUCTION |
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Mutation and inactivation of p53 are common in human cancers, occurring in over half of all human tumours (Harris, 1993; Hollstein et al., 1991
; Ko & Prives, 1996
; Levine, 1997
; Nigro et al., 1989
; Prives & Manley, 2001
; Ryan et al., 2001
). In response to various types of DNA damage and cell stress signals, the p53 tumour suppressor functions to integrate cellular responses including growth arrest at the G1 phase of the cell cycle or apoptosis (Amundson et al., 1998
; Bates & Vousden, 1999
; el-Deiry et al., 1993
; Gottlieb & Oren, 1998b
; Harper et al., 1993
; Polyak et al., 1997
; Selivanova & Wiman, 1995
; Shen & White, 2001
; Wu et al., 1999
). The biochemical activity required for p53 tumour suppression and the responses to DNA damage involve the ability of p53 to bind DNA in a sequence-specific manner and function as a transcriptional activator (el-Deiry et al., 1992
; Fields & Jang, 1990
; Liu & Kulesz-Martin, 2001
; Raycroft et al., 1990
). Expression of p53 in cells activates, through consensus p53 binding sites, a number of genes involved in p53-induced cell cycle arrest or apoptosis, including GADD45, WAF1, MDM2, Bax and PIG3 (Flatt et al., 2000
; Levine, 1997
; Yu et al., 1999
). The p53 protein is a key regulator of apoptosis under a variety of physiological and pathological conditions (Bates & Vousden, 1999
; Kastan et al., 1995
; Polyak et al., 1997
).
In view of recent results, it appears that p53 may also regulate cell cycle progression through targeted degradation of cell cycle regulatory proteins. Gottlieb & Oren (1998a) have reported that p53 facilitates pRb cleavage and degradation by activating the caspase protease pathway. Wild-type p53 has also been shown to accelerate degradation of cellular proteins including FLIP, which inhibits apoptosis (Fukazawa et al., 2001
);
-catenin, which is implicated in tumour development (Sadot et al., 2001
); delta-Np63, which is linked to accelerated tumorigenesis (Ratovitski et al., 2001
); and BRCA1, the breast and ovarian cancer susceptibility gene, which has been suggested to be involved in gene transcription and DNA repair (Irminger-Finger et al., 1999
; Choi, 2001
). In addition, Ravi et al. (2000)
reported that p53 enhances degradation of the hypoxia-inducible factor 1
, which is involved in tumour angiogenesis.
Tax-binding proteins, including CREB, p16, CBP/p300, NF-B, cyclin D and Mad1, which play pivotal roles in Tax transactivation and cell cycle regulation, have been identified (Adya et al., 1994
; Bex et al., 1998
; Brady, 1996
; Kanno et al., 1994
; Kashanchi et al., 1998
; Kwok et al., 1996
; Neuveut et al., 1998
; Suzuki et al., 1996
; Van Orden et al., 1999
). We previously reported the isolation of a Tax-binding protein, TRX (TAX1BP2), following screening of a Jurkat T-cell cDNA expression library. Direct interaction between Tax and TRX was demonstrated using Western blot and coimmunoprecipitation assays (Mireskandari et al., 1996
). We further demonstrated that TRX RNA was expressed ubiquitously in a number of cell lines and human tissues. In the present report, we demonstrate that the tumour suppressor p53 inhibits TRX expression by targeting and enhancing TRX degradation through a ubiquitin proteasome-mediated pathway. Similar to its ability to inhibit p53 transactivation, Tax inhibits the transcription-independent p53-mediated TRX proteolysis.
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METHODS |
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Plasmids.
The TRX cDNA (Mireskandari et al., 1996) was cloned into the PCRII vector (Invitrogen) and was amplified using Pfu DNA polymerase. The forward primer contained the 5'-coding sequences of TRX, with an additional ATG codon and KpnI site. The reverse primer contained 3'-coding sequences of TRX cDNA and a XhoI site. The PCR product was gel-purified and digested with KpnI and XhoI. The eukaryotic expression vector pcDNA3.1 His A or B (Invitrogen), containing the human cytomegalovirus (CMV) promoter and tag sequence for antibody detection, was digested with KpnI and XhoI and the TRX cDNA fragment inserted in-frame. TRX protein expression was tested by in vitro transcriptiontranslation using a rabbit reticulocyte lysate system (Promega), immunoprecipitation with a tag antibody (anti-Xpress, Invitrogen), or by Western blotting with anti-TRX antibody (rabbit polyclonal). TRX protein expression was also confirmed by transfecting Jurkat, Cos-1, HeLa and Saos-2 cells, followed by Western blotting and immunostaining with anti-tag or anti-TRX antibody. Tax expression vectors pc-Tax (wild-type) and Tax mutant M47 (L319R-L320S) were kindly provided by W. C. Greene (Smith & Greene, 1990
). The expression vector for p53 mutants p53R248W and p53R273H, and the p53 responsive element-containing reporter plasmids pG13-Luc and MDM2-Luc, were gifts from V. Vogelstein (Johns Hopkins University, Maryland, MD), and pCMVp53, which expresses wild-type (wt) human p53 from the HCMV immediate-early promoter, was a gift from S. J. Kim (National Cancer Institute, Bethesda, MD).
Transfection.
Transient transfection experiments with Cos-1, HeLa, Saos-2 and Jurkat cells were performed using either electroporation (Ausubel et al., 1989) or FuGene methods as described in the manufacturer's instructions (Roche Diagnostics). Briefly, cells were washed with RPMI without FBS and resuspended in 300 µl of the same media at a concentration of 5x106 per sample. The cells were electroporated (Bio-Rad Gene pulser) using 230 to 250 V at a capacitance of 975 µF. The amount of DNA transfected was normalized by the addition of vector control plasmid. TRX, Tax, p53, and p53 mutants R248W and R273H protein expression was assayed by Western blot as described below.
Western blotting.
Cells were washed with cold PBS, treated with PBS containing 2 mM EDTA, scraped and lysed in RIPA buffer (50 mM Tris, pH 8·0, 150 mM NaCl, 1 % Nonidet P-40, 0·5 % deoxycholate, 0·1 % SDS, containing 1 mM PMSF, aprotinin (1 µg ml-1), leupeptin (1 µg ml-1) and 5 mM sodium fluoride at 4 °C for 1 h. The lysate was cleared by centrifugation in a microcentrifuge at 14 000 r.p.m. for 15 min and the protein concentration was determined accordingly (Bio-Rad). Cell lysates (15 to 30 µg) were separated on 12 % or 4 to 20 % SDS-polyacrylamide gradient gels, transferred to an Immobilon membrane (Millipore) and assayed for TRX expression using anti-Xpress Tag antibody (Invitrogen). Tax, p53, mutant p53 (R248W and R273H) and the CMV immediate early 2 86 kDa gene product (IE-2) were detected using anti-Tax (Tab 172), anti-p53 (Do-1, pab421) and anti-IE-2 (rabbit polyclonal) antibodies, respectively. Antigenantibody complexes were detected using the enhanced chemiluminescence system (Amersham).
RNA isolation and Northern blotting.
RNA was isolated from transfected cells using TRIzol (Gibco-BRL). Fifteen µg of total RNA was used for each Northern blot analysis. RNA was vacuum-dried for 10 min, resuspended in denaturation buffer (10 mM phosphate buffer pH 7·0, 1x MOPS buffer, 50 % formamide, 2·1 M formaldehyde) and incubated at 65 °C for 5 min followed by quenching on ice. RNA loading buffer (2 µl) was added to each sample. Samples were run on a 1 % agarose gel containing 1x MOPS and 0·66 M formaldehyde and electrophoresis was performed at 50 V in 1x MOPS buffer. The RNA was blotted onto a nylon membrane (Micron Separation) using capillary action, and then fixed onto the membrane using a UV-Stratalinker 2400 (Stratagene). A 5' end-labelled TRX cDNA probe was used to detect the amount of TRX RNA in each sample. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA (Clontech) was used as a control for RNA loading.
Immunoprecipitation.
Cos-1 cells were co-transfected with TRX alone or in the presence of p53. Cells were pulsed with [35S]methionine and [35S]cysteine (200 µCi ml-1 or 500 µCi per 6 cm plate) for 30 min after 24 h of transfection, washed and chased for 3 h in complete medium. Samples were collected at 0, 0·5, 1·0, 2·0 and 3·0 h post-pulse. Cells were lysed in RIPA buffer, the protein concentration was determined and 500 µg of protein used for immunoprecipitation with an anti-Xpress (anti-Tag) antibody for the detection of TRX. The amount of labelled protein was quantified using the ImageQuant program (Molecular Dynamics).
Luciferase assay.
To assay for luciferase activity, Saos-2 cells were harvested 24 h after transfection by pG13-Luc or MDM2-Luc with wt p53 or mutants p53R248W or p53R273H. The cells were washed twice in cold PBS, and then lysed in 400 µl of Promega passive lysis buffer (Promega). Cells were then gently vortexed and kept on ice for 30 min. The supernatant was clarified by centrifugation at 14 000 r.p.m. for 5 min at 4 °C. The extract was kept at -80 °C until further use. The protein concentration was determined by the Bradford protein assay (Bio-Rad). Equal amounts of protein (5 to 20 µg) were added to 100 µl of luciferase substrate buffer according to the manufacturer's protocol (Promega); these samples were then analysed in a Berthold LB9500C Luminometer. Luminescence was measured in relative light units (RLU). Luciferase activity was expressed as average light units produced per µg of protein present in the specific cell lysate for each experiment. Each sample was assayed in triplicate and the average value was determined±standard deviation.
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RESULTS |
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Effect of p53 on TRX RNA expression
It was of interest to determine if the p53 effect on TRX expression was at the transcriptional or post-transcriptional level. Cos-1 cells were cotransfected with TRX/pcDNA3.1 in the presence or absence of p53. Total RNA was prepared and assayed for the level of TRX RNA with a TRX-specific probe. TRX mRNA was detected in cells transfected with TRX plasmid, but not the control cells (Fig. 3A, lanes 1 to 3). The level of TRX mRNA expression was similar in the presence and absence of p53 (lanes 2 and 4), indicating that p53 did not have any significant effect on TRX RNA expression. A control hybridization with the GAPDH probe demonstrated that equal amounts of RNA were present in all of the samples. The slight decrease in GAPDH RNA in lane 4 is not significant. These results suggest that the p53 effect is at the post-transcriptional level. Due to the high level of TRX mRNA produced from the replicating plasmid transfected into the cells, the endogenous 2·3 kb TRX mRNA is not detected in the exposure shown in Fig. 3
.
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TRX degradation is mediated through the proteasome pathway
Next, we wanted to determine whether p53-mediated TRX degradation was regulated through a specific proteolytic pathway. The proteasome-specific inhibitor MG132 and the cysteine protease inhibitor E64 were added to transfected cells at concentrations of 3 and 10 µM for 16 h. Consistent with previous reports, these conditions are not toxic to cells as shown when trypan blue exclusion is used to measure cell viability (Magae et al., 1997; Meriin et al., 1998
) (data not shown). Interestingly, the results show that the proteasome-specific inhibitor MG132 could block p53-mediated TRX protein degradation (Fig. 6
A, compare lanes 1, 3 and 7). Complete protection of TRX degradation was achieved at an MG132 concentration of 10 µM. In contrast, the cysteine protease inhibitor E64 (lanes 4 and 5) failed to inhibit TRX degradation. In parallel experiments, the calpain-specific inhibitor ALLN also failed to prevent p53-mediated TRX degradation (data not shown). These results suggest that p53 targets TRX proteolysis through the proteasome degradation pathway.
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Specificity of TRX protein degradation by p53
To determine if p53-mediated degradation of TRX was specific, we used the CMV IE-2 86 kDa gene product. IE-2 transactivates the CMV immediate early gene and has been shown to deregulate cell cycle and apoptosis pathways (Castillo et al., 2000; Salvant et al., 1998
; Wiebusch & Hagemeier, 1999
; Zhu et al., 1995
). The IE-2 expression vector was transfected into Saos-2 cells in the presence or absence of p53. As an experimental control, cells were transfected with TRX alone or in the presence of p53. Consistent with results presented above, the expression of TRX protein was reduced in the presence of p53 (Fig. 7
B, lanes 2 and 3). In contrast, the level of IE-2 protein expression was similar in the presence and absence of p53 (Fig. 7A
, lanes 4 and 5). Two background protein bands were routinely detected in the Western blots with the IE-2 antibody (Fig. 7A
). The level of reactivity, however, did not change significantly in the different experimental conditions and thus does not interfere with the interpretation of results.
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DISCUSSION |
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p53 may also regulate tumour development and cell cycle progression through targeted degradation of cell cycle regulatory proteins (Gottlieb & Oren, 1998a; Ratovitski et al., 2001
; Choi, 2001
; Ravi et al., 2000
). In the present study, we demonstrate that p53 promotes proteasome-dependent degradation of the cellular protein TRX. In cell cycle analysis, overexpression of TRX protein in a variety of cells did not result in cell cycle arrest at either the G1/S or G2/M border, suggesting that the function of TRX is not inhibition of cell cycle progression. Conversely, expression of TRX protein in cells blocked with hydroxyurea facilitated the progression of cells into S phase suggesting that TRX may act as a positive factor in G1/S progression (data not shown). Since expression of p53 in Saos-2 cells has been reported to increase G1/S arrest, it is interesting to speculate that p53 targets TRX for degradation in part to inhibit the G1/S transition. We have recently found that TRX functions as a coactivator, facilitating Tax transactivation of the HTLV-I LTR (data not shown). It will be of interest to determine if the cell cycle regulation is linked to the TRX transcription function.
To understand the mechanism of TRX degradation by p53, we have analysed p53 mutants which are transcriptionally inactive. The results of these studies demonstrate that TRX degradation is a transcription-independent function of p53, since p53R248W and p53R273H stimulate degradation. Ratovitski et al. (2001) showed similar results in the degradation of delta Np63 protein by p53. Of interest, delta Np63 degradation occurred via the caspase pathway. We used cysteine protease inhibitor E64, the 26S-proteasome inhibitor MG132 and the calpain 1 protease inhibitor ALLN. The cysteine protease inhibitor E64 and calpain 1 protease inhibitor ALLN failed to protect the p53-mediated TRX degradation. In contrast, proteasome-specific inhibitor MG132 blocked p53-mediated TRX degradation. The analysis of TRX protein by the PeptideCutter program revealed that there are no caspase (caspase1caspase10) cutting sites in the TRX protein. In contrast, chymotrypsin (30 cutting sites) and trypsin (20 cutting sites) protease sites are abundant.
The emerging model of the functional interaction of Tax and p53 interaction supports the ability of Tax to inhibit several functions of p53. We and others have previously shown that Tax inhibits the transactivation function of p53 (Ariumi et al., 2000; Cereseto et al., 1996
; Lemasson & Nyborg, 2001
; Mulloy et al., 1998
; Pise-Masison et al., 1998
, 2000
, 2001
; Suzuki et al., 1999
; Van Orden et al., 1999
). The data presented in this study demonstrate that Tax also blocks transcription-independent functions of p53. It will be of interest to further identify the functional consequences of TRX degradation, interaction with tumour suppressor p53 and its involvement in HTLV-I-induced leukaemogenesis.
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ACKNOWLEDGEMENTS |
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Received 5 August 2002;
accepted 27 November 2002.
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