The caspase-9 derived C-terminal fragment of cytokeratin 18 modulates topoisomerase action.
During early apoptosis the 33 amino acid C-terminal cytokeratin 18 (CK18) fragment is released by caspase-9 cleavage at the 393DALD/S site. This basic peptide relocates from the cytoskeleton to the nucleoplasm as shown by confocal laser scanning. It is shown that the C-terminal peptide modulates topoisomerase activity as measured by relaxation of plasmid DNA. In an in vitro assay recombinant caspase-induced chromatin condensation is inhibited by the peptide and at the electron microscopical level a clear inhibition of nucleolar breakdown was observed in its presence. We hypothesize that the C-terminal CK18 fragment exerts an effect in the nucleolus by stimulating rRNA transcription and processing via modulation of enzymatic activity of topoisomerase I. This leads to preservation of general transcriptional activity required to exert active steps during early stages of programmed cell death.
Schutte
B
B
Department of Molecular Cell Biology, University of Maastricht, Maastricht, The Netherlands. bert.schutte@molcelb.unimaas.nl
Henfling
M E R
ME
Verheyen
F K C P
FK
Li
G
G
Tolstonog
G V
GV
Ramaekers
F C S
FC
D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism / Q000473:pathology; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D053938:DNA Fragmentation; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D053538:Keratin-18 / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
D053538:Keratin-18; D010446:Peptide Fragments; D053453:Caspase 9; D004264:DNA Topoisomerases, Type I