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PMID: 11752447 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 26 ·2001-12-18 ·Pages 14985-90

Thomas DA, Scorrano L, Putcha GV, Korsmeyer SJ, Ley TJ

Abstract

Granzyme B (GzmB) is a serine protease that is used by activated cytotoxic T lymphocytes to induce target cell apoptosis. Although GzmB directly cleaves the Bcl2 family member BID on target cell entry, Bid-deficient (and Bax, Bak doubly deficient) cells are susceptible to GzmB-induced death, even though they fail to release cytochrome c from mitochondria. GzmB still induces mitochondrial depolarization in Bax, Bak double knockout cells without cytochrome c release or opening of the permeability transition pore. Because GzmB cannot directly cause depolarization of isolated mitochondria, novel intracellular factor(s) may be required for GzmB to depolarize mitochondria in situ. GzmB therefore utilizes two distinct mitochondrial pathways to amplify the proapoptotic signal that it delivers to target cells.

MeSH Terms
Animals Apoptosis/drug effects BH3 Interacting Domain Death Agonist Protein Carrier Proteins/physiology Cell Membrane Permeability Cytochrome c Group/metabolism Fluorescent Antibody Technique Granzymes Membrane Proteins/physiology Mice Mice, Inbred BALB C Mitochondria, Liver/drug effects,enzymology,physiology Proto-Oncogene Proteins/physiology Proto-Oncogene Proteins c-bcl-2 Serine Endopeptidases/pharmacology Subcellular Fractions/metabolism bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein
Chemicals
BH3 Interacting Domain Death Agonist Protein Bak1 protein, mouse Bax protein, mouse Bid protein, mouse Carrier Proteins Cytochrome c Group Membrane Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein Granzymes Gzmb protein, mouse Serine Endopeptidases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Thomas D A
Division of Oncology, Departments of Medicine and Genetics, Siteman Cancer Center, and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Scorrano L
Putcha G V
Korsmeyer S J
Ley T J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.261581498
Published
2001-12-18
Pages
14985-90
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC64970
Subset
IM
Grants
NIDDK NIH HHS · DK49786 · United States
NIDDK NIH HHS · R01 DK049786 · United States
NCI NIH HHS · R37 CA050239 · United States
NHLBI NIH HHS · T32 HL07088 · United States
NHLBI NIH HHS · T32 HL007088 · United States
NCI NIH HHS · R01 CA050239 · United States
NCI NIH HHS · CA50239 · United States
External Links
PubMed source DOI: 10.1073/pnas.261581498 PMC Full Text View journal details
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