Apoptotic Protease Activating Factor 1 (Apaf-1)-independent Cell Death Suppression by Bcl-2

doi:10.1084/jem.191.10.1709

Published online 15 May 2000.

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© The Rockefeller University Press, 0022-1007/2000/5/1709/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 10, May 15, 2000 1709-1720

Original Article

Apoptotic Protease Activating Factor 1 (Apaf-1)–independent Cell Death Suppression by Bcl-2

Misako Haraguchi^a, Seiji Torii^a, Shu-ichi Matsuzawa^a, Zhihua Xie^a, Shinichi Kitada^a, Stanislaw Krajewski^a, Hiroki Yoshida^b, Tak W. Mak^b, and John C. Reed^a
^a Burnham Institute Program on Apoptosis and Cell Death Regulation, La Jolla, California 92037
^b Department of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2C1

Correspondence to: John C. Reed, The Burnham Institute, Program on Apoptosis and Cell Death Regulation, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel:858-646-3140 Fax:858-646-3194 E-mail:jreed{at}burnham-inst.org.

Reportedly, antiapoptotic Bcl-2 family proteins suppress apoptosisby binding to and inhibiting members of the CED-4 family ofcaspase activators. To explore this question, we used embryonicstem (ES) cells in which one (-/+) or both (-/-) copies of thegene encoding apoptotic protease activating factor 1 (Apaf-1),a CED-4 homologue, were disrupted by homologous recombination.Stable clones of heterozygous (-/+) and homozygous (-/-) Apaf-1knockout ES cells that overexpressed Bcl-2 were generated. Withdrawalof serum growth factors or stimulation of heterozygous ES cellswith staurosporine (STS), ultraviolet (UV)B irradiation, etoposide(VP16), or cisplatin induced apoptosis followed by cell death(determined by failure to exclude propidium iodide dye). Thesecell death stimuli also induced activation of several typesof caspases and loss of mitochondrial membrane potential ( ${Delta}$ ${Psi}$ )in heterozygous (+/-) Apaf-1 knockout ES cells. In addition,overexpression of Bcl-2 protected against these events in Apaf-1–expressingES cells. In contrast, STS, UVB, and VP16 induced little orno caspase activation and apoptosis in homozygous (-/-) Apaf-1knockout ES cells. Nevertheless, Apaf-1–deficient ES cellssubjected to these cell death stimuli or deprived of growthfactors did eventually die through a nonapoptotic mechanismassociated with loss of ${Delta}$ ${Psi}$ . Moreover, Bcl-2 overprotection preserved ${Delta}$ ${Psi}$ , reduced the percentage of Apaf-1^-/- ES cells undergoing celldeath, and increased clonigenic survival. The extent of Bcl-2–mediatedcytoprotection was not significantly different for heterozygous(-/+) versus homozygous (-/-) Apaf-1 knockout cells. Furthermore,although Bcl-2 could be readily coimmunoprecipitated with Bax,associations with Apaf-1 were undetectable under conditionswhere Apaf-1 interactions with procaspase-9 were observed. Weconclude that Bcl-2 has cytoprotective functions independentof Apaf-1, preserving mitochondrial function through a caspase-independentmechanism.

Key Words: Bcl-2, apoptotic protease activating factor 1, caspase, apoptosis,mitochondria

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