Bcl-2 regulates amplification of caspase activation by cytochrome c

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 - https://www.scopus.com/pages/publications/0033545382

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

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

M3 - Article

C2 - 10021389

AN - SCOPUS:0033545382

SN - 0960-9822

VL - 9

SP - 147

EP - 150

JO - Current Biology

JF - Current Biology

IS - 3

ER -