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Cleavage of Bax enhances its cell death function.
1Department of Pathology, New York University School of Medicine and Kaplan Comprehensive Center, 550 First Avenue, New York, New York 10016, USA.
Experimental Cell Research
|April 25, 2000
Summary
Cleavage of the proapoptotic protein Bax (p21) into its p18 form enhances its cell death-inducing activity. This p18 Bax form promotes apoptosis more potently than p21 Bax, independent of the mitochondrial permeability transition pore.
Area of Science:
- Cellular biology
- Molecular biology
- Biochemistry
Background:
- The Bcl-2 protein family regulates apoptosis.
- Posttranslational modifications like cleavage alter protein function.
- Caspases cleave proapoptotic and prosurvival Bcl-2 proteins, modulating their activity.
Purpose of the Study:
- To investigate if the 18 kDa (p18) cleavage fragment of Bax exhibits increased cytotoxicity compared to the full-length 21 kDa (p21) form.
- To determine the role of caspases and the mitochondrial permeability transition pore in Bax-mediated apoptosis.
Main Methods:
- Transient transfection of human embryonic kidney 293T cells.
- Analysis of cell death induction by p21 Bax and p18 Bax.
- Assessment of apoptosis inhibition using pancaspase inhibitor Z-VAD-fmk and Cyclosporin A.
Main Results:
- The p18 form of Bax demonstrated a more potent ability to induce cell death than p21 Bax.
- Pancaspase inhibitor Z-VAD-fmk partially inhibited apoptosis induced by p18 Bax, but fully blocked apoptosis induced by p21 Bax.
- Cyclosporin A had no effect on Bax-mediated apoptosis, indicating independence from the mitochondrial permeability transition pore.
Conclusions:
- Cleavage of p21 Bax to the p18 form enhances its intrinsic cytotoxic properties.
- The p18 form of Bax may augment its cell death function at the mitochondria.
- Bax cleavage by calpain, rather than caspases, generates a more potent proapoptotic molecule.