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Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases

Beltinger, Christian, Fulda, Simone, Kammertoens, Thomas, Meyer, Eric, Uckert, Wolfgang, Debatin, Klaus-Michael·1999·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.96.15.8699
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Abstract

Suicide gene therapy systems such as the herpes simplex thymidine kinase/ganciclovir system (TK/GCV) may kill cancer cells by apoptosis through as yet undefined mechanisms. Here we show that TK/GCV treatment induces p53 accumulation and increases cell surface expression of CD95 and tumor necrosis factor receptor, which is likely to involve p53-mediated translocation of CD95 to the cell surface. TK/GCV-induced apoptosis involves CD95-L-independent CD95 aggregation leading to the formation of a Fas-associated death domain protein (FADD) and caspase-8-containing, death-inducing signaling complex. Dominant negative FADD, the caspase-8 inhibitor zIETD-fmk [Z-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone], and zVAD-fmk (Z-Val-Ala-Asp-fluoromethylketone) partially abrogate TK/GCV-induced apoptosis. In addition to apoptosis induction, TK/GCV treatment strongly sensitizes for CD95-L-, TNF-, and TNF-related, apoptosis-inducing, ligand (TRAIL)-induced cell death in constitutively resistant cells. These findings may be used to increase the efficacy of TK/GCV and other suicide gene therapy systems for the treatment of cancer.

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Metadata

Authors
Beltinger, C., Fulda, S., Kammertoens, T., Meyer, E., Uckert, W., & Debatin, K.-M.
Affiliations
Universitäts-Kinderklinik, 89075 Ulm, Germany; and Max-Delbrück Centrum für Molekulare Medizin, 13125 Berlin, Germany
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1999-07-20
Volume
96
Issue
15
Pages
8699-8704
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.96.15.8699
Cited by
143
References
0
Language
en

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CoChat. (2026). Citation check: Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. https://app.cochat.ai/papers/10.1073/pnas.96.15.8699
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Beltinger, C., Fulda, S., Kammertoens, T., Meyer, E., Uckert, W., & Debatin, K.-M. (1999). Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.96.15.8699