DOI: 10.1073/pnas.95.8.4386. Bcl-X <sub>L</sub> interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation

Bcl-X L interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation

10.1073/pnas.95.8.4386

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Recent studies indicate that Caenorhabditis elegans CED-4 interacts with and promotes the activation of the death protease CED-3, and that this activation is inhibited by CED-9. Here we show that a mammalian homolog of CED-4, Apaf-1, can associate with several death proteases, including caspase-4, caspase-8, caspase-9, and nematode CED-3 in mammalian cells. The interaction with caspase-9 was mediated by the N-terminal CED-4-like domain of Apaf-1. Expression of Apaf-1 enhanced the killing activity of caspase-9 that required the CED-4-like domain of Apaf-1. Furthermore, Apaf-1 promoted the processing and activation of caspase-9 in vivo . Bcl-X L , an antiapoptotic member of the Bcl-2 family, was shown to physically interact with Apaf-1 and caspase-9 in mammalian cells. The association of Apaf-1 with Bcl-X L was mediated through both its CED-4-like domain and the C-terminal domain containing WD-40 repeats. Expression of Bcl-X L inhibited the association of Apaf-1 with caspase-9 in mammalian cells. Significantly, recombinant Bcl-X L purified from Escherichia coli or insect cells inhibited Apaf-1-dependent processing of caspase-9. Furthermore, Bcl-X L failed to inhibit caspase-9 processing mediated by a constitutively active Apaf-1 mutant, suggesting that Bcl-X L regulates caspase-9 through Apaf-1. These experiments demonstrate that Bcl-X L associates with caspase-9 and Apaf-1, and show that Bcl-X L inhibits the maturation of caspase-9 mediated by Apaf-1, a process that is evolutionarily conserved from nematodes to humans.

Bibliography

Hu, Y., Benedict, M. A., Wu, D., Inohara, N., & NÃºÃ±ez, G. (1998). Bcl-X L interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proceedings of the National Academy of Sciences, 95(8), 4386â4391.

Authors 5

Yuanming Hu (first)
Mary A. Benedict (additional)
Dayang Wu (additional)
Naohiro Inohara (additional)
Gabriel Núñez (additional)

References 37 Referenced 422

10.1126/science.7878464
10.1101/gad.10.1.1
10.1016/0959-437X(94)90076-F
10.1016/0092-8674(93)90485-9
10.1038/356494a0
10.1101/gad.10.5.578
10.1126/science.275.5303.1126
10.1126/science.275.5303.1122
10.1038/385653a0
10.1074/jbc.272.34.21449
10.1016/S0960-9822(06)00216-8
10.1038/41913
Cohen G. M. (1997) Biochem J. 326 (Pt. 1) 1–16. (10.1042/bj3260001)
10.1126/science.275.5303.1081
10.1016/0092-8674(94)90506-1
10.1074/jbc.271.9.4573
10.1074/jbc.271.28.16850
10.1016/S0092-8674(00)80501-2
10.1016/S0968-0004(97)01043-8
10.1016/S0092-8674(00)80434-1
10.1016/0092-8674(93)90508-N
10.1073/pnas.94.20.10717
10.1128/mcb.12.10.4634-4642.1992
10.1126/science.278.5338.687
10.1016/S0092-8674(00)80085-9
10.1038/385086a0
10.1016/S0092-8674(00)81265-9
10.1016/S0092-8674(00)81266-0
10.1126/science.275.5303.1129
10.1126/science.275.5303.1132
10.1073/pnas.94.13.6939
C N Kim, X Wang, Y Huang, A M Ibrado, L Liu, G Fang, K Bhalla Cancer Res 57, 3115–3120 (1997). / Cancer Res by Kim C N (1997)
10.1016/S0092-8674(00)80450-X
10.1074/jbc.272.48.29995
10.1074/jbc.272.48.30299
10.1002/j.1460-2075.1996.tb00788.x
10.1073/pnas.86.24.9886

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:40 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 3:44 p.m.)
Indexed	1 month, 2 weeks ago (July 11, 2025, 6:46 a.m.)
Issued	27 years, 4 months ago (April 14, 1998)
Published	27 years, 4 months ago (April 14, 1998)
Published Online	27 years, 4 months ago (April 14, 1998)
Published Print	27 years, 4 months ago (April 14, 1998)

Funders 0

None

BibTeX

@article{Hu_1998, title={Bcl-X L interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation}, volume={95}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.95.8.4386}, DOI={10.1073/pnas.95.8.4386}, number={8}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Hu, Yuanming and Benedict, Mary A. and Wu, Dayang and Inohara, Naohiro and Núñez, Gabriel}, year={1998}, month=apr, pages={4386–4391} }

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