An Endoplasmic Reticulum Stress-specific Caspase Cascade in Apoptosis

By N. Morishima, K. Nakanishi, Hiromi Takenouchi, T. Shibata, Y. Yasuhiko. Journal of Biological Chemistry, 2002

616 citations recorded by the source corpus.

Activation of caspase-12 from procaspase-12 is specifically induced by insult to the endoplasmic reticulum (ER) (Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B. A., and Yuan, J. (2000) Nature 403, 98–103), yet the functional consequences of caspase-12 activation have been unclear. We have shown that recombinant caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. The activated caspase-9 catalyzes cleavage of procaspase-3, which is inhibitable by a caspase-9-specific inhibitor. Although cytochrome creleased from mitochondria has been believed to be required for caspase-9 activation during apoptosis (Zou, H., Henzel, W. J., Liu, X., Lutschg, A., and Wang, X. (1997) Cell 90, 405–413, Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X. (1997)Cell 91, 479–489), caspase-9 as well as caspase-12 and -3 are activated in cytochrome c-free cytosols in murine myoblast cells under ER stress. These results suggest that caspase-12 can activate caspase-9 without involvement of cytochrome c. To examine the role of caspase-12 in the activation of downstream caspases, we used a caspase-12-binding protein, which we identified in a yeast two-hybrid screen, for regulation of caspase-12 activation. The binding protein protects procaspase-12 from processing in vitro. Stable expression of the binding protein renders procaspase-12 insensitive to ER stress, thereby suppressing apoptosis and the activation of caspase-9 and -3. These data suggest that procaspase-9 is a substrate of caspase-12 and that ER stress triggers a specific cascade involving caspase-12, -9, and -3 in a cytochromec-independent manner.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2dc3746e1c9fa93b12a978063bc88142f68d2cf3

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In Cell Biology

1. M. Boyce
2. Junying Yuan
3. G. Hotamışlıgil
4. R. Kaufman

In Epidemiology

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2. R. Hotchkiss
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In Molecular Biology

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Citations in the corpus

• Apoptosis and caspases regulate death and inflammation in sepsis (2006, background): “, several investigative groups reported that caspase-12 mediates apoptosis in mouse models of endoplasmic-reticulum stress; for example, as occurs during calcium overloa”
• A decade of caspases (2003, background): “Thus far, calpain and caspase-7 have been proposed to activate caspase-12 (Nakagawa and Yuan, 2000; Rao et al., 2001), whereas caspase-12 was proposed to mediate cytochrome c-independent activation of caspase-9 (Morishima et al., 2002; Rao et al., 2002).”
• Regulation of apoptosis by endoplasmic reticulum pathways (2003, background): “Two groups recently reported that caspase-12 can directly cleave procas- pase-9 in vitro, leading to caspase-9-dependent activation of caspase-3 (Morishima et al., 2002; Rao et al., 2002).”
• Coupling endoplasmic reticulum stress to the cell death program (2004, background): “mitochondria (this is not to say that mitochondria may not be involved in the amplification of this pathway, simply that they are not required for its activation).(138,140,141) It is worth noting”