Bcl-2 regulates amplification of caspase activation by cytochrome c

Sabina C. Cosulich, Peter J. Savory, Paul R. Clarke

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Caspases, a family of specific proteases, have central roles in apoptosis [1]. Caspase activation in response to diverse apoptotic stimuli involves the relocalization of cytochrome c from mitochondria to the cytoplasm where it stimulates the proteolytic processing of caspase precursors. Cytochrome c release is controlled by members of the Bcl-2 family of apoptosis regulators [2,3]. The anti-apoptotic members Bcl-2 and Bcl-x(L) may also control caspase activation independently of cytochrome c relocalization or may inhibit a positive feedback mechanism [4-7]. Here, we investigate the role of Bcl-2 family proteins in the regulation of caspase activation using a model cell-free system. We found that Bcl-2 and Bcl-x(L) set a threshold in the amount of cytochrome c required to activate caspases, even in soluble extracts lacking mitochondria. Addition of dATP (which stimulates the procaspase-processing factor Apaf-1 [8,9]) overcame inhibition of caspase activation by Bcl-2, but did not prevent the control of cytochrome c release from mitochondria by Bcl-2. Cytochrome c release was accelerated by active caspase-3 and this positive feedback was negatively regulated by Bcl-2. These results provide evidence for a mechanism to amplify caspase activation that is suppressed at several distinct steps by Bcl-2, even after cytochrome c is released from mitochondria.

Original languageEnglish
Pages (from-to)147-150
Number of pages4
JournalCurrent Biology
Volume9
Issue number3
DOIs
Publication statusPublished - 11 Feb 1999

Fingerprint

cytochrome c
caspases
Caspases
Cytochromes c
Amplification
Chemical activation
Mitochondria
mitochondria
apoptosis
Apoptosis
Feedback
cell free system
Cell-Free System
caspase-3
Processing
Caspase 3
Cytoplasm
Peptide Hydrolases
proteinases
cytoplasm

Cite this

Cosulich, Sabina C. ; Savory, Peter J. ; Clarke, Paul R. / Bcl-2 regulates amplification of caspase activation by cytochrome c. In: Current Biology. 1999 ; Vol. 9, No. 3. pp. 147-150.
@article{ebd58d03a364480b9af310515f835018,
title = "Bcl-2 regulates amplification of caspase activation by cytochrome c",
abstract = "Caspases, a family of specific proteases, have central roles in apoptosis [1]. Caspase activation in response to diverse apoptotic stimuli involves the relocalization of cytochrome c from mitochondria to the cytoplasm where it stimulates the proteolytic processing of caspase precursors. Cytochrome c release is controlled by members of the Bcl-2 family of apoptosis regulators [2,3]. The anti-apoptotic members Bcl-2 and Bcl-x(L) may also control caspase activation independently of cytochrome c relocalization or may inhibit a positive feedback mechanism [4-7]. Here, we investigate the role of Bcl-2 family proteins in the regulation of caspase activation using a model cell-free system. We found that Bcl-2 and Bcl-x(L) set a threshold in the amount of cytochrome c required to activate caspases, even in soluble extracts lacking mitochondria. Addition of dATP (which stimulates the procaspase-processing factor Apaf-1 [8,9]) overcame inhibition of caspase activation by Bcl-2, but did not prevent the control of cytochrome c release from mitochondria by Bcl-2. Cytochrome c release was accelerated by active caspase-3 and this positive feedback was negatively regulated by Bcl-2. These results provide evidence for a mechanism to amplify caspase activation that is suppressed at several distinct steps by Bcl-2, even after cytochrome c is released from mitochondria.",
author = "Cosulich, {Sabina C.} and Savory, {Peter J.} and Clarke, {Paul R.}",
year = "1999",
month = "2",
day = "11",
doi = "10.1016/S0960-9822(99)80068-2",
language = "English",
volume = "9",
pages = "147--150",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Elsevier",
number = "3",

}

Bcl-2 regulates amplification of caspase activation by cytochrome c. / Cosulich, Sabina C.; Savory, Peter J.; Clarke, Paul R.

In: Current Biology, Vol. 9, No. 3, 11.02.1999, p. 147-150.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bcl-2 regulates amplification of caspase activation by cytochrome c

AU - Cosulich, Sabina C.

AU - Savory, Peter J.

AU - Clarke, Paul R.

PY - 1999/2/11

Y1 - 1999/2/11

N2 - Caspases, a family of specific proteases, have central roles in apoptosis [1]. Caspase activation in response to diverse apoptotic stimuli involves the relocalization of cytochrome c from mitochondria to the cytoplasm where it stimulates the proteolytic processing of caspase precursors. Cytochrome c release is controlled by members of the Bcl-2 family of apoptosis regulators [2,3]. The anti-apoptotic members Bcl-2 and Bcl-x(L) may also control caspase activation independently of cytochrome c relocalization or may inhibit a positive feedback mechanism [4-7]. Here, we investigate the role of Bcl-2 family proteins in the regulation of caspase activation using a model cell-free system. We found that Bcl-2 and Bcl-x(L) set a threshold in the amount of cytochrome c required to activate caspases, even in soluble extracts lacking mitochondria. Addition of dATP (which stimulates the procaspase-processing factor Apaf-1 [8,9]) overcame inhibition of caspase activation by Bcl-2, but did not prevent the control of cytochrome c release from mitochondria by Bcl-2. Cytochrome c release was accelerated by active caspase-3 and this positive feedback was negatively regulated by Bcl-2. These results provide evidence for a mechanism to amplify caspase activation that is suppressed at several distinct steps by Bcl-2, even after cytochrome c is released from mitochondria.

AB - Caspases, a family of specific proteases, have central roles in apoptosis [1]. Caspase activation in response to diverse apoptotic stimuli involves the relocalization of cytochrome c from mitochondria to the cytoplasm where it stimulates the proteolytic processing of caspase precursors. Cytochrome c release is controlled by members of the Bcl-2 family of apoptosis regulators [2,3]. The anti-apoptotic members Bcl-2 and Bcl-x(L) may also control caspase activation independently of cytochrome c relocalization or may inhibit a positive feedback mechanism [4-7]. Here, we investigate the role of Bcl-2 family proteins in the regulation of caspase activation using a model cell-free system. We found that Bcl-2 and Bcl-x(L) set a threshold in the amount of cytochrome c required to activate caspases, even in soluble extracts lacking mitochondria. Addition of dATP (which stimulates the procaspase-processing factor Apaf-1 [8,9]) overcame inhibition of caspase activation by Bcl-2, but did not prevent the control of cytochrome c release from mitochondria by Bcl-2. Cytochrome c release was accelerated by active caspase-3 and this positive feedback was negatively regulated by Bcl-2. These results provide evidence for a mechanism to amplify caspase activation that is suppressed at several distinct steps by Bcl-2, even after cytochrome c is released from mitochondria.

UR - http://www.scopus.com/inward/record.url?scp=0033545382&partnerID=8YFLogxK

U2 - 10.1016/S0960-9822(99)80068-2

DO - 10.1016/S0960-9822(99)80068-2

M3 - Article

VL - 9

SP - 147

EP - 150

JO - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 3

ER -