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Science 10 October 1997:
Vol. 278. no. 5336, pp. 294 - 298
DOI: 10.1126/science.278.5336.294
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Reports

Caspase-3-Generated Fragment of Gelsolin: Effector of Morphological Change in Apoptosis

Srinivas Kothakota, * Toshifumi Azuma, * Christoph Reinhard, Anke Klippel, Jay Tang, Keting Chu, Thomas J. McGarry, Marc W. Kirschner, Kirston Koths, David J. Kwiatkowski, dagger Lewis T. Williams

The caspase-3 (CPP32, apopain, YAMA) family of cysteinyl proteases has been implicated as key mediators of apoptosis in mammalian cells. Gelsolin was identified as a substrate for caspase-3 by screening the translation products of small complementary DNA pools for sensitivity to cleavage by caspase-3. Gelsolin was cleaved in vivo in a caspase-dependent manner in cells stimulated by Fas. Caspase-cleaved gelsolin severed actin filaments in vitro in a Ca2+-independent manner. Expression of the gelsolin cleavage product in multiple cell types caused the cells to round up, detach from the plate, and undergo nuclear fragmentation. Neutrophils isolated from mice lacking gelsolin had delayed onset of both blebbing and DNA fragmentation, following apoptosis induction, compared with wild-type neutrophils. Thus, cleaved gelsolin may be one physiological effector of morphologic change during apoptosis.

S. Kothakota, C. Reinhard, A. Klippel, K. Chu, K. Koths, L. T. Williams, Chiron Corporation, Emeryville, CA 94608, USA.
T. Azuma, J. Tang, D. J. Kwiatkowski, Division of Experimental Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
T. J. McGarry and M. W. Kirschner, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: kwiatkowski{at}calvin.bwh.harvard.edu

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Molecular Ordering of the Initial Signaling Events of CD95.
A. Algeciras-Schimnich, L. Shen, B. C. Barnhart, A. E. Murmann, J. K. Burkhardt, and M. E. Peter (2002)
Mol. Cell. Biol. 22, 207-220
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Vibrio vulnificus Cytolysin Induces Superoxide Anion-initiated Apoptotic Signaling Pathway in Human ECV304 Cells.
K.-B. Kwon, J.-Y. Yang, D.-G. Ryu, H.-W. Rho, J.-S. Kim, J.-W. Park, H.-R. Kim, and B.-H. Park (2001)
J. Biol. Chem. 276, 47518-47523
   Abstract »    Full Text »    PDF »
Characterization of Fortilin, a Novel Antiapoptotic Protein.
F. Li, D. Zhang, and K. Fujise (2001)
J. Biol. Chem. 276, 47542-47549
   Abstract »    Full Text »    PDF »
Cytochrome c release into cytosol with subsequent caspase activation during warm ischemia in rat liver.
J. Soeda, S. Miyagawa, K. Sano, J. Masumoto, S.'I. Taniguchi, and S. Kawasaki (2001)
Am J Physiol Gastrointest Liver Physiol 281, G1115-G1123
   Abstract »    Full Text »    PDF »
Expression of scinderin in megakaryoblastic leukemia cells induces differentiation, maturation, and apoptosis with release of plateletlike particles and inhibits proliferation and tumorigenesis.
R. Zunino, Q. Li, S. D. Rose, M. M. I. Romero-Benitez, T. Lejen, N. C. Brandan, and J.-M. Trifaro (2001)
Blood 98, 2210-2219
   Abstract »    Full Text »    PDF »
Cooperative Control of Akt Phosphorylation, bcl-2 Expression, and Apoptosis by Cytoskeletal Microfilaments and Microtubules in Capillary Endothelial Cells.
D. A. Flusberg, Y. Numaguchi, and D. E. Ingber (2001)
Mol. Biol. Cell 12, 3087-3094
   Abstract »    Full Text »    PDF »
Proteolysis of the Docking Protein HEF1 and Implications for Focal Adhesion Dynamics.
G. M. O'Neill and E. A. Golemis (2001)
Mol. Cell. Biol. 21, 5094-5108
   Abstract »    Full Text »    PDF »
Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase III{alpha}.
R. Freire, F. d'Adda di Fagagna, L. Wu, G. Pedrazzi, I. Stagljar, I. D. Hickson, and S. P. Jackson (2001)
Nucleic Acids Res. 29, 3172-3180
   Abstract »    Full Text »    PDF »
Induction of Caspase-Dependent Apoptosis in Cultured Cells by the Avian Coronavirus Infectious Bronchitis Virus.
C. Liu, H. Y. Xu, and D. X. Liu (2001)
J. Virol. 75, 6402-6409
   Abstract »    Full Text »
Differential effect of MLC kinase in TNF-{alpha}-induced endothelial cell apoptosis and barrier dysfunction.
I. Petrache, A. D. Verin, M. T. Crow, A. Birukova, F. Liu, and J. G. N. Garcia (2001)
Am J Physiol Lung Cell Mol Physiol 280, L1168-L1178
   Abstract »    Full Text »    PDF »
Deficiency of Caspase-3 in MCF7 Cells Blocks Bax-mediated Nuclear Fragmentation but not Cell Death.
S. Kagawa, J. Gu, T. Honda, T. J. McDonnell, S. G. Swisher, J. A. Roth, and B. Fang (2001)
Clin. Cancer Res. 7, 1474-1480
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Characterization of the Caspase Inhibitor IDN-1965 in a Model of Apoptosis-Associated Liver Injury.
N. C. Hoglen, B. P. Hirakawa, C. D. Fisher, S. Weeks, A. Srinivasan, A. M. Wong, K. L. Valentino, K. J. Tomaselli, X. Bai, D. S. Karanewsky, et al. (2001)
J. Pharmacol. Exp. Ther. 297, 811-818
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Initiation of Apoptosis by Actin Cytoskeletal Derangement in Human Airway Epithelial Cells.
S. R. White, P. Williams, K. R. Wojcik, S. Sun, P. S. Hiemstra, K. F. Rabe, and D. R. Dorscheid (2001)
Am. J. Respir. Cell Mol. Biol. 24, 282-294
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PECAM-1 shedding during apoptosis generates a membrane-anchored truncated molecule with unique signaling characteristics.
N. ILAN, A. MOHSENIN, L. CHEUNG, and J. A. MADRI (2001)
FASEB J 15, 362-372
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Cleavage of Mitogen-Activated Protein Kinases in Human Neutrophils Undergoing Apoptosis: Role in Decreased Responsiveness to Inflammatory Cytokines.
K. Suzuki, T. Hasegawa, C. Sakamoto, Y.-M. Zhou, F. Hato, M. Hino, N. Tatsumi, and S. Kitagawa (2001)
J. Immunol. 166, 1185-1192
   Abstract »    Full Text »    PDF »
Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices.
G. Davis, K. Pintar Allen, R Salazar, and S. Maxwell (2001)
J. Cell Sci. 114, 917-930
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Reconstitution of Caspase 3 Sensitizes MCF-7 Breast Cancer Cells to Doxorubicin- and Etoposide-induced Apoptosis.
X.-H. Yang, T. L. Sladek, X. Liu, B. R. Butler, C. J. Froelich, and A. D. Thor (2001)
Cancer Res. 61, 348-354
   Abstract »    Full Text »


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