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J. Biol. Chem., Vol. 280, Issue 2, 857-860, January 14, 2005

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Nuclear Translocation of Caspase-3 Is Dependent on Its Proteolytic Activation and Recognition of a Substrate-like Protein(s)^*

Shinji Kamada¶||, Ushio Kikkawa, Yoshihide Tsujimoto¶, and Tony Hunter**

From the Molecular and Cell Biology Laboratory, The Salk Institute, La Jolla, California 92037, the Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan, and the ^¶Laboratory of Molecular Genetics, Department of Post-Genomics and Diseases, Osaka University Medical School and Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565–0871, Japan

Caspase-3 is thought to play an important role(s) in the nuclear morphological changes that occur in apoptotic cells and many nuclear substrates for caspase-3 have been identified despite the cytoplasmic localization of procaspase-3. Therefore, whether activated caspase-3 is localized in the nuclei and how active caspase-3 has access to its nuclear targets are important and unresolved questions. Here we confirmed nuclear localizations for both caspase-3-p17 and caspase-3-p12 subunits of active caspase in apoptotic cells using subcellular fractionation analysis. We also prepared polyclonal and monoclonal antibodies specific for active caspase-3 to define the subcellular localization of active caspase-3. Immunocytochemical observations using anti-active caspase-3 antibodies showed nuclear accumulation of active caspase-3 during apoptosis. In addition, caspase-3, but not caspase-7, translocated from the cytoplasm into the nucleus after induction of apoptosis. Mutations at the cleavage site between the p17 and p12 subunits and the substrate recognition site for the P3 amino acid of the DXXD substrate cleavage motif inhibited nuclear translocation of caspase-3, indicating that nuclear transport of active caspase-3 required proteolytic activation and substrate recognition. These results suggest that active caspase-3 is translocated in association with a substrate-like protein(s) from the cytoplasm into the nucleus during progression through apoptosis.

Received for publication, November 19, 2004

^* This work was supported in part by grants-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture of Japan (to S. K.) and by Public Health Service Grants CA82863 and CA14195 from the NCI (to T. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Results, and Fig. S1.

^** Frank and Else Schilling American Cancer Society Professor. To whom correspondence may be addressed: Molecular and Cell Biology Laboratory, The Salk Inst., 10010 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-453-4100; Fax: 858-457-4765; E-mail: hunter{at}salk.edu.

^|| To whom correspondence may be addressed. Tel.: 81-78-803-5965; Fax: 81-78-803-5972; E-mail: skamada{at}kobe-u.ac.jp.

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