Chemotherapeutic drugs cause DNA damage and kill cancer cells mainly by apoptosis. p53 mediates apoptosis after DNA damage. To explore the pathway of p53-dependent cell death, we investigated if p53-dependent apoptosis after DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated hepatoma, gastric cancer, colon cancer, and breast cancer cell lines upon treatment with different anticancer agents known to act via p53 accumulation. Cisplatin, mitomycin, methotrexate, mitoxantrone, doxorubicin, and bleomycin at concentrations present in the sera of patients during therapy led to an upregulation of both CD95 receptor and CD95 ligand. Induction of the CD95 ligand occurred in p53 wild-type (wt), p53 mutant (mt), and p53 deficient (p53−/−) cell lines and at wt and mt conformation of temperature-sensitive p53 mutants. In contrast, upregulation of the CD95 receptor was observed only in cells with wt p53, not in cells with mt or without any p53. Restitution of inducible wt p53 function restored the ability of p53−/− Hep3B cells to upregulate the CD95 receptor in response to anticancer drugs. This rendered the cells sensitive to CD95-mediated apoptosis. In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, whereas mt p53 failed to induce apoptosis via activation of the CD95 gene. These observations provide a mechanistic explanation for the ability of p53 to contribute to tumor progression and to resistance of cancer cells to chemotherapy.
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7 December 1998
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December 07 1998
p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs
Martina Müller,
Martina Müller
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Sylvia Wilder,
Sylvia Wilder
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Detlev Bannasch,
Detlev Bannasch
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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David Israeli,
David Israeli
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Katrin Lehlbach,
Katrin Lehlbach
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Min Li-Weber,
Min Li-Weber
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Scott L. Friedman,
Scott L. Friedman
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Peter R. Galle,
Peter R. Galle
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Wolfgang Stremmel,
Wolfgang Stremmel
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Moshe Oren,
Moshe Oren
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Peter H. Krammer
Peter H. Krammer
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
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Martina Müller
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Sylvia Wilder
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Detlev Bannasch
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
David Israeli
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Katrin Lehlbach
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Min Li-Weber
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Scott L. Friedman
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Peter R. Galle
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Wolfgang Stremmel
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Moshe Oren
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Peter H. Krammer
From the *Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, 69115 Heidelberg, Germany; the ‡Tumor Immunology Program and §Department of Cytogenetics, German Cancer Research Center, 69120 Heidelberg, Germany; the ‖Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel; and the ¶Division of Liver Diseases, Mount Sinai Medical Center, New York 10029
Address correspondence to Peter H. Krammer, Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-423718; Fax: 49-6221-411715; E-mail: [email protected]
Received:
May 19 1998
Revision Received:
September 14 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (11): 2033–2045.
Article history
Received:
May 19 1998
Revision Received:
September 14 1998
Citation
Martina Müller, Sylvia Wilder, Detlev Bannasch, David Israeli, Katrin Lehlbach, Min Li-Weber, Scott L. Friedman, Peter R. Galle, Wolfgang Stremmel, Moshe Oren, Peter H. Krammer; p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs . J Exp Med 7 December 1998; 188 (11): 2033–2045. doi: https://doi.org/10.1084/jem.188.11.2033
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