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Reciprocal Down-Regulation of P53 and SOD2 Gene Expression ± Implication in P53 Mediated Apoptosis

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Reciprocal Down-Regulation of P53 and SOD2 Gene Expression ± Implication in P53 Mediated Apoptosis Oncogene (2001) 20, 430 ± 439 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Reciprocal down-regulation of p53 and SOD2 gene expression ± implication in p53 mediated apoptosis Pascal Drane1, Anne Bravard2,Ve ronique Bouvard1 and Evelyne May*,1 1Commissariat aÁ l'Energie Atomique (CEA), Laboratoire de CanceÂrogeneÁse MoleÂculaire, UMR217 CEA-CNRS, DRR, DSV, BP6 92265 Fontenay-aux-Roses Cedex, France; 2Commissariat aÁ l'Energie Atomique (CEA), Laboratoire de Radiobiologie Cellulaire, DRR, DSV, BP6 92265 Fontenay-aux-Roses Cedex, France p53 regulates the transcription of a number of genes cells containing damaged DNA. These functions are among which are dierent redox-related genes. It has controlled, at least in part, by the property of p53 to been proposed that these genes can induce a cellular act as a transcriptional activator. In addition to oxidative stress leading to p53-dependent apoptosis stimulate the expression of cellular genes involved in (Polyak et al., 1997). MnSOD, the product of super- p53-dependent G1 arrest and apoptosis, p53 promotes oxide dismutase 2 (SOD2) gene, is one of the major the transcription of genes predicted to generate or cellular defences against oxidative stress. We demon- respond to oxidative stress suggesting that p53 strate here that p53 is able to repress SOD2 gene activation can result in an oxidative stress leading to expression and that this repression takes place at apoptosis (Polyak et al., 1997). promoter level. We show the importance of this On the other hand, p53 has been reported to repress regulation for the p53 function, by demonstrating that the expression of a number of genes. Several mechan- an overexpression of MnSOD decreases p53-mediated isms have been proposed including interference with induction of apoptosis. Moreover, we demonstrate that initiation of transcription (Farmer et al., 1996; Wang MnSOD overexpression decreases p53-gene expression and Beck, 1998), binding to p53 responsive element at the promoter level. These ®ndings raise the hypothesis (p53RE) (Ori et al., 1998; Lee et al., 1999) or complex that p53 and SOD2 genes are mutually regulated leading formation with histone deacetylases (Murphy et al., to the modulation of various cellular processes including 1999). apoptosis. Oncogene (2001) 20, 430±439. The mitochondrial enzyme manganese superoxide dismutase (MnSOD), involved in ROS detoxi®cation, .7 Keywords: p53; superoxide dismutase; apoptosis; gene catalyses the dismutation of superoxide radical (O2 ) regulation; NF-kB into hydrogen peroxide (H2O2) and oxygen (O2). There are two other SOD enzymes expressed in human cells, a cytosolic CuZnSOD (McCord and Fridovich, 1969) Introduction and an extracellular CuZnSOD (Marklund et al., 1982). Interestingly, while mice with disruption of one The transcription factor p53 plays a pivotal role in of either form of CuZnSOD gene are viable, MnSOD maintaining the genomic integrity of cells. In response knockout mice have been shown to develop cardio- to various stresses, p53 has been shown to be activated myopathy and neonatal lethality (Huang et al., 1999). and stabilized. Activation of p53 results from post- This argues for MnSOD being one of the major translational events such as acetylation, phosphoryla- cellular defences against oxidative stress. tion and/or interaction with cellular proteins (May and MnSOD is encoded by the nuclear SOD2 gene May, 1999). The stabilisation of p53 is caused localized in the human chromosome 6q25 (Church et primarily by an increase in its half-life after post- al., 1992). Two main observations place SOD2 as a translational modi®cations that might be distinct from candidate tumor suppressor gene: the loss of hetero- those involved in p53 activation (Chernov et al., 1998). zygosity of chromosome region 6q found in about 40 Accumulation of p53 could also result from an up- percent of human malignant melanomas (Oberley and regulation of its gene transcription rate involving, in Oberley, 1997) and the deletion of the long arm of particular, the NF-kB transcription factor (Hellin et chromosome 6 identi®ed in SV40 transformed human al., 1998). ®broblast (Bravard et al., 1992). In addition, MnSOD In response to genotoxic stress and depending on the overexpression suppresses the tumorigenicity of human cell-type, p53 response causes two major cellular melanoma cells (Church et al., 1993), breast cancer cells events, either cell cycle arrest or programmed cell (Li et al., 1995) and glioma cells (Zhong et al., 1997). death (apoptosis), both preventing the propagation of Since both p53 and MnSOD appear to be involved in oxidative stress response, we have been interested in investigating a possible functional interaction between these two proteins. We present evidence that wt-p53 *Correspondence: E May Received 2 October 2000; revised 14 November 2000; accepted 14 down-regulates SOD2 gene expression at the promoter November 2000 level and that, in turn, an overexpression of MnSOD Cross-regulation of p53 and SOD2 gene expression P Drane et al 431 decreases the transcription level from p53 promoter and inhibits the p53-mediated induction of apoptosis. Results Constitutive SOD2 gene expression in MCF-7 and MCF-7/R-A1 cells MCF-7 and MCF-7/R-A1 are two related cell lines expressing wt-p53 and the mutant p53R280K, respec- tively (Cai et al., 1997). The wt status of p53 protein expressed in the parental MCF-7 cells used in this study was con®rmed by transient expression experi- ments using the luciferase reporter gene placed under the control of either wt (pE1B-hWAF1) or mutated (pE1B-hWAF1-mut) waf1-p53RE. Results presented in Figure 1a show in MCF-7 cells, a 700-fold increase of luciferase activity from wt waf1-p53RE compared to that obtained with the mutated one. By contrast and in agreement with the mutated status of p53 no such eect is observed with MCF-7/R-A1. By analysing similar cellular models, it has been reported that wt-p53 might participate to the constitu- tive expression of p53-target genes (Tang et al., 1998). We then took advantage of this cellular model to analyse a possible eect of wt-p53 on the constitutive expression of SOD2 gene. Representative Northern blots for waf1 and MnSOD2 mRNA are presented in Figure 1b. In agreement with previous study (Tang et al., 1998), the expression of waf1 is signi®cantly higher in MCF-7 than in MCF-7/R-A1, indicating that endogenous p53 might regulate the cellular waf1 gene expression. Inverse results are obtained for MnSOD (Figure 1b). The 4 kb-MnSOD mRNA species is Figure 1 Characterization of MCF-7 and the derivative MCF-7/ detectable in both cell lines, however, its intensity is R-A1 cell lines for: (a) their ability to activate transcription from the waf1 p53RE, (b) SOD2 mRNA level and (c) MnSOD activity. signi®cantly lower in MCF-7 than in MCF-7/R-A1. (a) MCF-7 and MCF-7/R-A1 cell lines were transfected with the Furthermore, in agreement with mRNA levels, the luciferase expression plasmid pE1B-hWAF1 (wt-p53RE) or pE1B- MnSOD activity is at least ®vefold lower in MCF-7 hWAF1-mut (having a mutated p53RE). Luciferase activity was than in MCF-7/R-A1 cellular extracts (Figure 1c). It is measured 24 h after transfection and normalized relative to the interesting to note that the high level of MnSOD in Renilla luciferase activity. (b) Twenty mg of total RNA extracted from con¯uent culture of MCF-7 and MCF-7/R-A1 cells were MCF-7/R-A1 correlates with an increase in their cell electrophoresed and transferred to Hybond N membrane doubling time compared to the parental MCF-7 cell (Amersham). Blot was successively hybridized with waf1 and line (data not shown). This is in agreement with the SOD2 cDNA probes. The loading was controlled by ethidium fact that MnSOD overexpression alters cell growth (Li bromide staining. (c) Activity of MnSOD was determined in both et al., 1995). We then hypothesised that SOD2 gene cell lines as described in Materials and methods expression might be down-regulated by wt p53. clearly showed that PMA treatment leads to a signi®cant Activation of endogenous wt-p53 down-regulates the increase in MnSOD mRNA level in both MCF-7 SOD2 gene expression in MCF-7 (compare lanes 1 and 2) and MCF-7/R-A1 cells To further analyse the interaction between SOD2 (compare lanes 5 and 6). This is noticeable for both 1 expression and p53, we asked whether physiological and 4 kb mRNA species, generated by alternate activation of p53 by g-irradiation leads to a decrease of polyadenylation (Wispe et al., 1989). Interestingly, the steady-state level of MnSOD mRNA in MCF-7, SOD2 mRNA level is further increased in PMA- using MCF-7/R-A1 cells as negative control. To over- pretreated MCF-7/RA-1 cells, following g-irradiation come the diculty due to the very low level of MnSOD at a dose of 6 Gy (Figure 2a, compare lanes 6 and 8). In mRNA (Figure 1b), the cells were pretreated with PMA, contrast, a comparable treatment of MCF-7 leads to a a phorbol ester, that causes a consistent increase in signi®cant decrease of SOD2 mRNA level (Figure 2a, MnSOD mRNA level (Li et al., 1998). According to compare lanes 2 and 4). Both decrease (MCF-7) and these published data, results presented in Figure 2a increase (MCF-7/RA-1) in MnSOD mRNA level Oncogene Cross-regulation of p53 and SOD2 gene expression P Drane et al 432 Figure 2 Eect of g-radiation on basal and PMA-induced SOD2 mRNA level in MCF-7 and MCF-7/R-A1 (a) and eect of PMA pre-treatment on g-radiation-induced accumulation (b) and activation (c) of MCF-7 endogenous wt-p53.
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