Nuclear accumulation of p53 in response to treatment with DNA-damaging agents

Hess, Ralf D.; Plaumann, B.; Lutum, Annegret Schulze; Haessler, Christel; Heinz, Barbara; Fritsche, Michael; Brandner, Gerhard

doi:10.1016/0378-4274(94)90008-6

Cited by 24 publications

(12 citation statements)

References 11 publications

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“…We examined the expression level of ATBF1 mRNA in AFP-gastric cancer cells and found it to be elevated after treatment with MMC. Treatment of mammalian cells with MMC causes an increase in the cellular p53 level (10) and resulted in the activation of p21 (Waf1/Cip1) transcription. Recently, we revealed that the promoter p21 (Waf1/Cip1) was activated by ATBF1 in the hepatoma Hep G2 cell line (12).…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to Killer T Cells of Gastric Cancer Cells Enhanced by Mitomycin‐C Involves Induction of ATBF1 and Activation of p21 (Waf1/Cip1) Promoter

Miura

Kataoka

Joh

et al. 2004

Microbiology and Immunology

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Alpha‐fetoprotein (AFP) expression is observed in embryonic tissues and, the expression of this protein is absent in normal adult tissues. The re‐elevation of serum AFP strongly suggests generation of a malignant tumor in an adult. We demonstrated here that AFP‐producing gastric cancer (AFP‐gastric cancer) could be treated by a combination therapy with a low dose of Mitomycin‐C (MMC) and lymphokine‐activated killer T (LAK‐T) cells. Treatment with MMC of AFP‐gastric cancer cells enhanced their susceptibility to LAK‐T cells and induced ATBF1 gene expression. We revealed here a novel signal pathway for regulation of the cell cycle of AFP‐gastric cancer cells through ATBF1, which enhances the promoter activity of the p21 (Waf1/Cip1) gene. Immunoprecipitation revealed the direct interaction between ATBF1 and p53. Overexpressed ATBF1 stimulated p21 (Waf1/Cip1) promoter activity up to 4‐fold compared with basal activity. The expression level of ATBF1 mRNA was doubled by MMC (0.05 μg/ml) treatment. The MMC treatment and ATBF1 overexpression synergistically activated the p21 (Waf1/Cip1) promoter activity in a dose‐dependent manner up to 7‐fold compared with basal activity.

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Section: Discussionmentioning

confidence: 99%

Susceptibility to Killer T Cells of Gastric Cancer Cells Enhanced by Mitomycin‐C Involves Induction of ATBF1 and Activation of p21 (Waf1/Cip1) Promoter

Miura

Kataoka

Joh

et al. 2004

Microbiology and Immunology

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“…MC induces DNA damage in the form of DNA cross-links and monofunctional DNA alkylation products in various bacterial and mammalian cells and tissues (2)(3)(4)(5)(6)(7). Treatment of mammalian cells with MC causes an increase in the cellular p53 level (8). In cells, MC is enzymatically reduced, yielding reactive species that are capable of producing radicals through redox cycling, as well as a variety of DNA adducts.…”

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confidence: 99%

Differential Activation of p53 by the Various Adducts of Mitomycin C

Abbas

Olivier

Lopez

et al. 2002

Journal of Biological Chemistry

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Mitomycin C (MC) is a cytotoxic chemotherapeutic agent that causes DNA damage in the form of DNA crosslinks as well as a variety of DNA monoadducts and is known to induce p53. The various DNA adducts formed upon treatment of mouse mammary tumor cells with MC as well as 10-decarbamoyl MC (DMC) and 2,7-diaminomitosene (2,7-DAM), the major MC metabolite, have been elucidated. The cytotoxicity of DMC parallels closely that of MC in a number of rodent cell lines tested, whereas 2,7-DAM is relatively noncytotoxic. In this study, we investigate the ability of MC, DMC, and 2,7-DAM to activate p53 at equidose concentrations by treating tissue culture cell lines with the three mitomycins. Whereas MC and DMC induced p53 protein levels and increased the levels of p21 and Gadd45 mRNA, 2,7-DAM did not. Furthermore, MC and DMC, but not 2,7-DAM, were able to induce apoptosis efficiently in ML-1 cells. Therefore the 2,7-DAM monoadducts were unable to activate the p53 pathway. Interestingly, DMC was able to initiate apoptosis via a p53-independent pathway whereas MC was not. This is the first finding that adducts of a multiadduct type DNA-damaging agent are differentially recognized by DNA damage sensor pathways.

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“…In contrast, the DNA damage response is strong in various non-lymphoid rodent and primate cells (Fritsche et al, 1991(Fritsche et al, , 1993. Nevertheless, even these signi®cantly inducible p53 levels are low in comparison with those occurring constitutively in the nucleus of untreated SV40-transformed cells (Hess et al, 1994).…”

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confidence: 89%

DNA-damage-inducible p53 activity in SV40-transformed cells

Hess

Brandner

1997

Oncogene

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The biological state of the tumour suppressor proteins Rb and p53 is altered in papillomavirus-and SV40-transformed cells, due to interaction with the DNA tumour virus oncogene proteins E6/E7 and the tumour (T) antigen. Thus, the DNA damage response function of p53, a crucial feature of the tumour suppressor p53, might be considered as inactive. To investigate this subject, C57SV and VLM, two SV40-transformed murine cell lines enharboring constitutively high nuclear p53 and SV40 large T antigen levels, were treated with mitomycin C. Mitomycin C is known for its activity to elicit DNA damage, followed by nuclear accumulation of biologically active p53. Surprisingly, the nuclear p53 level signi®cantly increased in mitomycin-C-treated C57SV cells and to a lesser degree in VLM cells. In addition, expression of p21WAF1 protein was induced in C57SV and VLM cells. This indicates a possible DNAdamage-elicited p53 activation. Finally, nuclear extracts of mitomycin-C-treated C57SV and VLM cells, but not of untreated cells, exhibited PAb421-enhanced speci®c DNA-binding activity of p53, as proven by gel shift analysis. Thus, DNA damage induced essential biological functions typical for wild-type p53 in the SV40-transformed cell lines examined so far.

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Nuclear accumulation of p53 in response to treatment with DNA-damaging agents

Cited by 24 publications

References 11 publications

Susceptibility to Killer T Cells of Gastric Cancer Cells Enhanced by Mitomycin‐C Involves Induction of ATBF1 and Activation of p21 (Waf1/Cip1) Promoter

Susceptibility to Killer T Cells of Gastric Cancer Cells Enhanced by Mitomycin‐C Involves Induction of ATBF1 and Activation of p21 (Waf1/Cip1) Promoter

Differential Activation of p53 by the Various Adducts of Mitomycin C

DNA-damage-inducible p53 activity in SV40-transformed cells

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