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Delineation of the caspase-9 signaling cascade

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Abstract

In the intrinsic apoptosis pathway, mitochondrial disruption leads to the release of multiple apoptosis signaling molecules, triggering both caspase-dependent and -independent cell death. The release of cytochrome c induces the formation of the apoptosome, resulting in caspase-9 activation. Multiple caspases are activated downstream of caspase-9, however, the precise order of caspase activation downstream of caspase-9 in intact cells has not been completely resolved. To characterize the caspase-9 signaling cascade in intact cells, we employed chemically induced dimerization to activate caspase-9 specifically. Dimerization of caspase-9 led to rapid activation of effector caspases, including caspases-3, -6 and -7, as well as initiator caspases, including caspases-2, -8 and -10, in H9 and Jurkat cells. Knockdown of caspase-3 suppressed caspase-9-induced processing of the other caspases downstream of caspase-9. Silencing of caspase-6 partially inhibited caspase-9-mediated processing of caspases-2, -3 and -10, while silencing of caspase-7 partially inhibited caspase-9-induced processing of caspase-2, -3, -6 and -10. In contrast, deficiency in caspase-2, -8 or -10 did not significantly affect the caspase-9-induced caspase cascade. Our data provide novel insights into the ordering of a caspase signaling network downstream of caspase-9 in intact cells during apoptosis.

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Acknowledgements

We thank Karen Lin for technical assistance. This work was supported by grants from the American Heart Association (M.C and J.W.), the American Society of Hematology (M.C) and the NIH (J.W.), and by a Ruth L. Kirschstein National Research Service Award (A.D.G.).

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  1. Department of Immunology, Baylor College of Medicine, One Baylor Plaza, N920, Houston, TX, 77030, USA

    Alan D. Guerrero, Min Chen & Jin Wang

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  1. Alan D. Guerrero
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  2. Min Chen
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Correspondence to Min Chen or Jin Wang.

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Guerrero, A.D., Chen, M. & Wang, J. Delineation of the caspase-9 signaling cascade. Apoptosis 13, 177–186 (2008). https://doi.org/10.1007/s10495-007-0139-8

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