Benzo[a]pyrene Activates the Human p53 Gene through Induction of Nuclear Factor κB Activity

Pei, Xin-Hai; Nakanishi, Yoichi; Takayama, K.; Bai, Feng; Hara, Nobuyuki

doi:10.1074/jbc.274.49.35240

Cited by 85 publications

(53 citation statements)

References 40 publications

(39 reference statements)

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“…For this purpose, plucp53NFkBmut was constructed from pluc-mp53 recombinant by inactivating the p53-promoter NF-kB site. In agreement with already published data (Pei et al, 1999), inactivation of NF-kB site signi®cantly diminishes the level in the luciferase gene expression from the p53-promoter (Figure 6d, control). Furthermore, the co-expression of IkBa inhibits the luciferase expression from pluc-mp53 but not from plucp53NFkBmut (Figure 6d,+IkBa).…”

Section: Overexpression Of Mnsod Inhibits P53-dependent Apoptosissupporting

confidence: 80%

“…Considering the fact that MnSOD has been shown to modulate NF-kB activity (Li et al, 1998), and that NF-kB regulates p53 promoter activity (Wu and Lozano, 1994;Hellin et al, 1998;Pei et al, 1999), we were led to analyse the eect of an overexpression of MnSOD on p53 promoter activity. We then cotransfected pluc-mp53, a plasmid encoding the luciferase reporter gene under the control of the mouse p53 promoter, with increasing amounts of MnSOD expression vector, in H1299 cells.…”

Section: Overexpression Of Mnsod Inhibits P53-dependent Apoptosismentioning

confidence: 99%

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Reciprocal down-regulation of p53 and SOD2 gene expression–implication in p53 mediated apoptosis

et al. 2001

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p53 regulates the transcription of a number of genes among which are dierent redox-related genes. It has been proposed that these genes can induce a cellular oxidative stress leading to p53-dependent apoptosis (Polyak et al., 1997). MnSOD, the product of superoxide dismutase 2 (SOD2) gene, is one of the major cellular defences against oxidative stress. We demonstrate here that p53 is able to repress SOD2 gene expression and that this repression takes place at promoter level. We show the importance of this regulation for the p53 function, by demonstrating that an overexpression of MnSOD decreases p53-mediated induction of apoptosis. Moreover, we demonstrate that MnSOD overexpression decreases p53-gene expression at the promoter level. These ®ndings raise the hypothesis that p53 and SOD2 genes are mutually regulated leading to the modulation of various cellular processes including apoptosis. Oncogene (2001) 20, 430 ± 439.

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Section: Overexpression Of Mnsod Inhibits P53-dependent Apoptosissupporting

confidence: 80%

Section: Overexpression Of Mnsod Inhibits P53-dependent Apoptosismentioning

confidence: 99%

Reciprocal down-regulation of p53 and SOD2 gene expression–implication in p53 mediated apoptosis

et al. 2001

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“…In this line of evidence, it was previously reported that p53 gene expression is activated through NF-kB after Benzo(a)pyrene treatment. 15 The idea that p53 accumulation results from a higher transcription rate rather than from the protein stabilization is emphasised by the fact that TNFa did not induce p53 phosphorylation at Ser-20. Indeed, phosphorylation at Ser-20 has been shown to inhibit p53 interaction with the ubiquitin-ligase MDM2, preventing p53 degradation by the proteasome pathway and thereby promoting p53 stabilization.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, NF-kB also regulates the expression of the tumour suppressor gene p53, 13 although the role of this regulation is not well understood. 14,15 A large number of evidence places the p53 suppressor gene at a nodal point in the regulation of diverse stress responses. Indeed, a number of cellular stresses including DNA damage, heat shock, hypoxia, hyperoxia, metabolic changes, oncogene activation, and others, converge on p53 protein and cause its activation and stabilization.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of an inactive form of p53 protein in cells treated with TNFα

et al. 2002

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In MCF-7 cells, TNFa induces a G1 arrest with an increased expression of p21/Waf1, an activation of NF-kB and an accumulation of p53. NF-kB and p53 are two transcriptional factors known to activate p21/Waf1 gene expression. Here we show that p53 inhibition has no effect on p21/Waf1 mRNA accumulation following TNFa treatment. In contrast, inactivation of NF-kB inhibits p21/Waf1 expression without affecting G1 arrest. The fact that p21/Waf1 gene expression is still stimulatedwhenp53isinactivatedstronglysuggeststhatTNFa induces accumulation of an inactive form of p53 protein. This assumption was further supported by the following observations: (i) the p53 DNA-binding activity to its consensus sequence was not stimulated following TNFa treatment, (ii) phosphorylation at Ser-15, -20 or -392 was not detected in response to TNFa, (iii) the transcription rate of Ddb2, another p53 target gene, was not stimulated by TNFa. Finally, the accumulation of p53 in the nuclei of TNFa-treated MCF-7 cells was concomitant with an increase in p53 mRNA level, suggesting a regulation at the transcription level.

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“…The transcription factors shown to positively regulate p53 transcription include c-myc (Kirch et al, 1999;Lee and Rho, 2000), NF-kB (Pei et al, 1999;Benoit et al, 2000), YY1/NF1 (Lee et al, 1998(Lee et al, , 1999Nayak and Das, 1999), Ap1 (Kirch et al, 1999), and the HoxA5 homeobox containing gene product (Raman et al, 2000). Members of the PAX family are the only mammalian nuclear proteins shown to repress p53 transcription through a binding site present in the ®rst non-coding exon (Stuart et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

The critical role of the PE21 element in oncostatin M-mediated transcriptional repression of the p53 tumor suppressor gene in breast cancer cells

et al. 2001

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Cytokine oncostatin M (OM) exerts growth-inhibitory and di erentiative e ects on breast cancer cells. Previously we showed that the transcription from the p53 gene in breast cancer cells was down regulated by OM. To elucidate the molecular mechanisms underlying the OM e ect on p53 transcription, in this study, we dissected the p53 promoter region and analysed the p53 promoter activity in breast tumor cells. We showed that treatment of MCF-7 cells with OM induced a dose-and time-dependent suppression of p53 promoter activity. The p53 promoter activity was decreased to 35% of control at 24 h and further decreased to 20% at 48 h by OM at concentrations of 5 ng/ml and higher. Deletion of the 5'-¯anking region of the p53 promoter from 7426 to 797 did not a ect the OM e ect. However, further deletion to 740 completely abolished the repressive e ect of OM. The p53 promoter region 796 to 741 contains NF-kB and c-myc binding sites, and a newly identi®ed UV-inducible element PE21. Mutations to disrupt NF-kB binding or c-myc binding to the p53 promoter decreased the basal promoter activity without a ecting the OM-mediated suppression, whereas mutation at the PE21 motif totally abolished the OM e ect. We further demonstrated that insertion of PE21 element upstream of the thymidine kinase minimal promoter generated an OM response analogous to that of the p53 promoter. Finally, we detected the speci®c binding of a nuclear protein with a molecular mass of 87 kDa to the PE21 motif. Taken together, we demonstrate that OM inhibits the transcription of the p53 gene through the PE21 element. Thus, the PE21 element is functionally involved in p53 transcription regulated by UV-induction and OM suppression. Oncogene (2001) 20, 8193 ± 8202.

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Benzo[a]pyrene Activates the Human p53 Gene through Induction of Nuclear Factor κB Activity

Abstract: p53 is known to be recruited in response to DNAdamaging genotoxic stress and plays an important role in maintaining the integrity of the genome. In the present study, the effect of a potent lung cancer carcinogen, benzo

Cited by 85 publications

References 40 publications

Reciprocal down-regulation of p53 and SOD2 gene expression–implication in p53 mediated apoptosis

Reciprocal down-regulation of p53 and SOD2 gene expression–implication in p53 mediated apoptosis

Accumulation of an inactive form of p53 protein in cells treated with TNFα

The critical role of the PE21 element in oncostatin M-mediated transcriptional repression of the p53 tumor suppressor gene in breast cancer cells

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