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Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Beltinger, Christian P. Fulda, Simone Kammertoens, Thomas Meyer, Evelyne. Uckert, Wolfgang Debatin, K. M. |
| Copyright Year | 1999 |
| 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. |
| Starting Page | 5 |
| Ending Page | 10 |
| Page Count | 6 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.pnas.org/content/96/15/8699.full.pdf |
| PubMed reference number | 10411938v1 |
| Volume Number | 96 |
| Issue Number | 15 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Aminolevulinic Acid CD95 Antigens Cell Death FASLG protein, human Fas-Associated Death Domain Protein Ganciclovir Herpes Simplex Infections Isoleucine Ligands Neoplasms Positive Regulation of Apoptosis Receptor Aggregation Thymidine Kinase Tumor Necrosis Factor Receptor Valine benzyloxycarbonyl-Phe-Ala-fluormethylketone caspase caspase-8 death-inducing signaling complex location |
| Content Type | Text |
| Resource Type | Article |
