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Caspase-9 processing by caspase-3 via a feedback amplification loop in vivo
E Fujita1, J Egashira, K Urase
1Division of Development and Differentiation, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan.
Cell Death and Differentiation
|September 11, 2001
Summary
Caspase-9 activation involves initial autoprocessing and subsequent caspase-3 feedback amplification. This loop is crucial for full caspase activation and programmed cell death in neurons.
Area of Science:
- Cell Biology
- Molecular Biology
- Apoptosis Research
Background:
- Caspase-9 autoprocessing is understood, but its in vivo processing by caspase-3 via a feedback loop is less clear.
- Understanding caspase activation pathways is vital for apoptosis research.
Purpose of the Study:
- To investigate the biological significance of caspase-9 processing by caspase-3 in vivo.
- To elucidate the role of the caspase-3 feedback loop in caspase-9 activation and apoptosis.
Main Methods:
- Developed specific antisera to detect activated mouse caspase-9.
- Utilized caspase-9- and caspase-3-deficient mouse embryonic fibroblasts.
- Assayed caspase-3-like (Ac-DEVD-MCA) and caspase-9-like (Ac-LEHD-MCA) cleavage activities.
Main Results:
- Mouse caspase-9 undergoes low-level autoprocessing at D(353) and D(368) during staurosporine-induced apoptosis.
- Activated caspase-3 preferentially processes D(368) and D(168) sites of caspase-9, forming a feedback amplification loop.
- Caspase-9 autoprocessing is essential for initial caspase-3 activation, while the feedback loop ensures full activation of both caspases.
- This feedback loop is critical for programmed cell death in dorsal root ganglia neurons.
Conclusions:
- A feedback amplification loop involving caspase-3 processing of caspase-9 is essential for robust caspase activation.
- This pathway plays a significant role in neuronal programmed cell death during embryonic development.