This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dinsdale, D. Articles by Peter, M. E. Search for Related Content PubMed PubMed Citation Articles by Dinsdale, D. Articles by Peter, M. E.

(American Journal of Pathology. 2004;164:395-407.)
© 2004 American Society for Investigative Pathology

Intermediate Filaments Control the Intracellular Distribution of Caspases During Apoptosis

David Dinsdale^*, Justine C. Lee, Grant Dewson^*, Gerald M. Cohen^* and Marcus E. Peter

From the Medical Research Council Toxicology Unit,^* Leicester, United Kingdom; and the Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois

Caspases are responsible for a cascade of events controlling the disassembly of apoptotic cells. We now demonstrate that caspase-9 is activated at an early stage of apoptosis in epithelial cells and all its detectable, catalytically active large subunits (both the p35 and p37) are concentrated on cytokeratin fibrils. Immunolabeling of distinctive neoepitopes, exposed by cleavage of procaspase-9 at either Asp315 or Asp330, was co-localized on these fibrils with active caspase-3, caspase-cleaved cytokeratin-18, death-effector-domain containing DNA-binding protein and ubiquitin. Cytokeratin filaments may thus provide a scaffold whereby active subunits of caspase-9 can activate caspase-3 which, in turn, can activate more caspase-9 so forming an amplification loop to facilitate cleavage of cytokeratin-18, disruption of the cytoskeleton and the ensuing formation of cytoplasmic inclusions. These inclusions, formed from the collapse of fibrils, together with their associated components, also contain ubiquitinated proteins, vimentin, heat-shock protein 72, and tumor necrosis factor receptor type-1-associated death domain protein. Many of their constituents, including active caspases, remain sequestered within these inclusions, even after detergent treatment and isolation. Thus, such inclusions do not merely accumulate disrupted cytokeratins but also sequestrate potentially noxious proteins that could injure healthy neighboring cells.

This article has been cited by other articles:

				Y.-M. Lin, Y.-R. Chen, J.-R. Lin, W.-J. Wang, A. Inoko, M. Inagaki, Y.-C. Wu, and R.-H. Chen eIF3k regulates apoptosis in epithelial cells by releasing caspase 3 from keratin-containing inclusions J. Cell Sci., July 15, 2008; 121(14): 2382 - 2393. [Abstract] [Full Text] [PDF]

				D. Barcaroli, D. Dinsdale, M. H. Neale, L. Bongiorno-Borbone, M. Ranalli, E. Munarriz, A. E. Sayan, J. M. McWilliam, T. M. Smith, E. Fava, et al. FLASH is an essential component of Cajal bodies PNAS, October 3, 2006; 103(40): 14802 - 14807. [Abstract] [Full Text] [PDF]

				P. W. Fisher, F. Salloum, A. Das, H. Hyder, and R. C. Kukreja Phosphodiesterase-5 Inhibition With Sildenafil Attenuates Cardiomyocyte Apoptosis and Left Ventricular Dysfunction in a Chronic Model of Doxorubicin Cardiotoxicity Circulation, April 5, 2005; 111(13): 1601 - 1610. [Abstract] [Full Text] [PDF]

				H. Holubec, C. M. Payne, H. Bernstein, K. Dvorakova, C. Bernstein, C. N. Waltmire, J. A. Warneke, and H. Garewal Assessment of Apoptosis by Immunohistochemical Markers Compared to Cellular Morphology in Ex Vivo-stressed Colonic Mucosa J. Histochem. Cytochem., February 1, 2005; 53(2): 229 - 235. [Abstract] [Full Text] [PDF]