p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs
10.1084/jem.188.11.2033
Crossref journal-article
Rockefeller University Press
The Journal of Experimental Medicine (291)
Abstract

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.

Bibliography

Müller, M., Wilder, S., Bannasch, D., Israeli, D., Lehlbach, K., Li-Weber, M., Friedman, S. L., Galle, P. R., Stremmel, W., Oren, M., & Krammer, P. H. (1998). p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs. The Journal of Experimental Medicine, 188(11), 2033–2045.

Authors 11
  1. Martina Müller (first)
  2. Sylvia Wilder (additional)
  3. Detlev Bannasch (additional)
  4. David Israeli (additional)
  5. Katrin Lehlbach (additional)
  6. Min Li-Weber (additional)
  7. Scott L. Friedman (additional)
  8. Peter R. Galle (additional)
  9. Wolfgang Stremmel (additional)
  10. Moshe Oren (additional)
  11. Peter H. Krammer (additional)
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Dates
Type When
Created 23 years, 1 month ago (July 26, 2002, 12:48 p.m.)
Deposited 2 years, 1 month ago (July 25, 2023, 5:17 a.m.)
Indexed 1 hour, 3 minutes ago (Aug. 26, 2025, 7:34 p.m.)
Issued 26 years, 8 months ago (Dec. 7, 1998)
Published 26 years, 8 months ago (Dec. 7, 1998)
Published Online 26 years, 8 months ago (Dec. 7, 1998)
Published Print 26 years, 8 months ago (Dec. 7, 1998)
Funders 0

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@article{M_ller_1998, title={p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs}, volume={188}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.188.11.2033}, DOI={10.1084/jem.188.11.2033}, number={11}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Müller, Martina and Wilder, Sylvia and Bannasch, Detlev and Israeli, David and Lehlbach, Katrin and Li-Weber, Min and Friedman, Scott L. and Galle, Peter R. and Stremmel, Wolfgang and Oren, Moshe and Krammer, Peter H.}, year={1998}, month=dec, pages={2033–2045} }