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Volume 272, Number 37, Issue of September 12, 1997 pp. 23111-23116
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Requirement of the Caspase-3/CPP32 Protease Cascade for Apoptotic Death following Cytokine Deprivation in Hematopoietic Cells

(Received for publication, March 10, 1997, and in revised form, June 23, 1997)

Takayuki Ohta , Taisei Kinoshita , Mikihiko Naito ^§ , Tadashige Nozaki ^¶ , Mitsuko Masutani ^¶ , Takashi Tsuruo ^§ and Atsushi Miyajima

From the  Laboratory of Cellular Biosynthesis and ^§ Laboratory of Biomedical Research, Institute of Molecular and Cellular Bioscience, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113, Japan, ^¶ Biochemistry Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104, Japan

Hematopoietic cytokines transduce cell survival signals, which are distinct from the signals necessary for the stimulation of DNA synthesis. Recently, the Ras and phosphatidylinositol 3-kinase pathways have been shown to play important roles in preventing apoptosis in various cell types, e.g. hematopoietic cells and neuronal cells. Withdrawal of cytokine(s), in turn, results in rapid inactivation of these survival pathways and eventually leads to cell death accompanied by the hallmarks of apoptosis. However, the mechanism of cell death caused by cytokine deprivation has not been fully elucidated. In this study, we demonstrate that caspase-3/CPP32, a member of the caspase/interleukin-1-converting enzyme family, is activated upon interleukin (IL)-3 deprivation in IL-3-dependent cells as well as IL-2 deprivation in IL-2-dependent cells. In addition, poly(ADP-ribose) polymerase, a cellular substrate for the caspase family proteases, was degraded into apoptotic fragments in both cell lines after cytokine removal. Furthermore, inhibition of a caspase family protease by synthetic peptides suppressed apoptotic death. These results indicate that the activation of a caspase-like protease(s) is required for the progression of apoptosis following cytokine deprivation. However, readdition of IL-3 did not restore the proliferative potential of the cells that survived in the presence of the peptide inhibitor after IL-3 depletion. Therefore, cellular commitment to apoptosis appears to precede the activation of a caspase-like protease(s).

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