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- Title
Identification of p21 as a target of cycloheximide-mediated facilitation of CD95-mediated apoptosis in human malignant glioma cells.
- Authors
Glaser, Tamara; Wagenknecht, Bettina; Weller, Michael
- Abstract
Human glioma cell lines differ in their requirement for the inhibition of protein synthesis to activate the CD95-dependent killing pathway. CD95 ligand (CD95L) induced mitochondrial cytochrome c release and processing of caspases 3, 7, 8 and 9 in LN-18 cells in the absence of an inhibitor of protein synthesis, cycloheximide (CHX). These biochemical changes were observed in LN-229 cells only in the presence of CHX. The viral caspase inhibitor, cytokine response modifier (crm)-A, inhibited mitochondrial cytochrome c release, caspase processing and cell death under all conditions. Ectopic expression of BCL-XL prevented processing of caspase 8 in LN-18 cells but not in LN-229 cells. Thus, caspase 8 activation is amplified through the release of cytochrome c in LN-18 cells but occurs mainly at the receptor in LN-229 cells. In contrast to BCL-2, BCL-XL, X-linked inhibitor-of-apoptosis protein (XIAP) and FLICE-inhibitory protein (FLIP), the levels of the cyclin-dependent kinase (CDK) inhibitor, p21Waf/Cip1, rapidly decreased in response to CHX. P21 antisense oligonucleotides promoted caspase activation and mitochondrial cytochrome c release and induced strong sensitization to CD95-mediated apoptosis. These data place potentiating effects of CHX (i) to the activation of caspase 8 at the receptor in LN-229 cells as well as (ii) to a down-stream target at least in LN-18 cells, but probably both cell lines, that may be identical with p21Waf/Cip1. Oncogene (2001) 20, 4757–4767.
- Subjects
APOPTOSIS; GLIOMAS; CYTOCHROME c; PROTEIN synthesis
- Publication
Oncogene, 2001, Vol 20, Issue 35, p4757
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204498