Dependence of granzyme B-mediated cell death on a pathway regulated by Bcl-2 or its viral homolog, BHRF1.

Glu) Bcl-2, or wild-type Bcl-2 directed to the plasma membrane conferred no protection. Overexpression of Bcl-2 resulted in inhibition of multiple parameters of apoptosis in response to purified perforin and granzyme B, including DNA fragmentation, changes in light scatter profile indicating cell shrinkage and increased refractivity, loss of mitochondrial membrane potential and inhibited colony formation in clonogenic assays. Nevertheless, when exposed to cytotoxic lymphocytes, FDC-P1 and YAC-1 cells overexpressing Bcl-2 remained susceptible to death imparted by cytolytic granules, irrespective of whether the granules contained granzyme B. Thus, alternative granzyme B-independent pathways can be activated by intact lymphocytes to overcome Bcl-2-like inhibitors of apoptosis, enabling CTLs to overcome potential viral blocks to granzyme B-mediated cell death. -->
Substance Nomenclature: 0 (BHRF1 protein, Human herpesvirus 4)
0 (Proto-Oncogene Proteins c-bcl-2)
0 (Viral Proteins)
EC 3.4.21.- (GZMB protein, human)
EC 3.4.21.- (Granzymes)
EC 3.4.21.- (Gzmb protein, mouse)
EC 3.4.21.- (Serine Endopeptidases)
Entry Date(s): Date Created: 20010330 Date Completed: 20010524 Latest Revision: 20061115
Update Code: 20231215
DOI: 10.1038/sj.cdd.4400725
PMID: 11279544
Autor: Davis JE; John Connell Laboratory, The Austin Research Institute, Studley Road, Heidelberg, 3084, Australia., Sutton VR, Smyth MJ, Trapani JA
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2000 Oct; Vol. 7 (10), pp. 973-83.
DOI: 10.1038/sj.cdd.4400725
Abstrakt: The molecular pathways responsible for apoptosis in response to granzyme B have remained unresolved. Here we present data supporting the notion that granzyme B-mediated cell death is largely dependent on a pathway that is inhibitable by Bcl-2 or its viral analog BHRF1. We used a panel of stably transfected FDC-P1 mouse myeloid cell lines to show that overexpression of functional, wild-type Bcl-2 or BHRF1 rescued cells from granzyme B-mediated apoptosis, whereas mutated (Gly145-->Glu) Bcl-2, or wild-type Bcl-2 directed to the plasma membrane conferred no protection. Overexpression of Bcl-2 resulted in inhibition of multiple parameters of apoptosis in response to purified perforin and granzyme B, including DNA fragmentation, changes in light scatter profile indicating cell shrinkage and increased refractivity, loss of mitochondrial membrane potential and inhibited colony formation in clonogenic assays. Nevertheless, when exposed to cytotoxic lymphocytes, FDC-P1 and YAC-1 cells overexpressing Bcl-2 remained susceptible to death imparted by cytolytic granules, irrespective of whether the granules contained granzyme B. Thus, alternative granzyme B-independent pathways can be activated by intact lymphocytes to overcome Bcl-2-like inhibitors of apoptosis, enabling CTLs to overcome potential viral blocks to granzyme B-mediated cell death.
Databáze: MEDLINE
Externí odkaz: