Header

UZH-Logo

Maintenance Infos

Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7


Pik Ki, Chan. Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7. 2020, University of Zurich, Faculty of Medicine.

Abstract

Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.

Abstract

Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.

Statistics

Downloads

1 download since deposited on 27 Jan 2021
1 download since 12 months
Detailed statistics

Additional indexing

Item Type:Dissertation (monographical)
Referees:Bornhaser Beat, Bourquin Jean-Pierre
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
UZH Dissertations
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2020
Deposited On:27 Jan 2021 09:54
Last Modified:28 Jan 2021 04:39
OA Status:Closed
Free access at:Related URL. An embargo period may apply.
Related URLs:https://www.zora.uzh.ch/id/eprint/177433/

Download

Closed Access: Download allowed only for UZH members

Content: Published Version
Filetype: PDF - Registered users only until 1 December 2023
Size: 3MB
Embargo till: 2023-12-01