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J. Exp. Med.,
Volume 188, Number 11, December 7, 1998 2033-2045
By
From the * Department of Internal Medicine IV, Hepatology and Gastroenterology,
University Hospital, 69115 Heidelberg, Germany; the 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 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
/) 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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