A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells

Objective Bryostatin-1 and related diacylglycerol (DAG) analogues activate RasGRPs in lymphocytes, thereby activating Ras and mimicking some aspects of immune receptor signaling. To define the role of RasGRPs in lymphocyte apoptosis and to identify potential therapeutic uses for DAG analogues in lym...

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Bibliographic Details
Published in:Experimental hematology 2009, Vol.37 (1), p.122-134.e2
Main Authors: Stang, Stacey L, Lopez-Campistrous, Ana, Song, Xiaohua, Dower, Nancy A, Blumberg, Peter M, Wender, Paul A, Stone, James C
Format: Article
Language:English
Subjects:
Advanced Basic Science
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - physiology
Apoptosis Regulatory Proteins - metabolism
B-Lymphocytes - metabolism
bcl-2-Associated X Protein - metabolism
Bcl-2-Like Protein 11
Bryostatins - pharmacology
Cell Line, Tumor
Cell Membrane Permeability - drug effects
Cell Membrane Permeability - physiology
DNA-Binding Proteins - metabolism
Extracellular Signal-Regulated MAP Kinases - metabolism
Guanine Nucleotide Exchange Factors - metabolism
Hematology, Oncology and Palliative Medicine
Humans
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Membrane Proteins - metabolism
Mice
Mitochondrial Membranes - metabolism
Phosphorylation - drug effects
Proto-Oncogene Proteins - metabolism
Receptors, Antigen, B-Cell - metabolism
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Summary:Objective Bryostatin-1 and related diacylglycerol (DAG) analogues activate RasGRPs in lymphocytes, thereby activating Ras and mimicking some aspects of immune receptor signaling. To define the role of RasGRPs in lymphocyte apoptosis and to identify potential therapeutic uses for DAG analogues in lymphocyte disorders, we characterized the response of lymphoma-derived cell lines to DAG analogues. Materials and Methods Human lymphoma-derived B cell lines and mouse primary B cells were treated with bryostatin-1 or its synthetic analogue “pico.” Ras signaling partners and Bcl-2 family members were studied with biochemical assays. Cellular responses were monitored using growth and apoptosis assays. Results Stimulation of B cells with DAG analogues results in activation of protein kinase C/RasGRP-Ras-Raf-Mek-Erk signaling and phosphorylation of the proapoptotic BH3-only protein Bim. In vitro, Bim is phosphorylated by Erk on sites previously associated with increased apoptotic activity. In Toledo B cells derived from a non-Hodgkin's lymphoma (B-NHL), DAG analogue stimulation leads to extensive apoptosis. Apoptosis can be suppressed by either downregulation of Bim or overexpression of Bcl-2. It is associated with the formation of Bak−Bax complexes and increased mitochondrial membrane permeability. Toledo B-NHL cell apoptosis shows a striking dependence on sustained signaling. Conclusion In B cells, Erk activation leads directly to phosphorylation of Bim on sites associated with activation of Bim. In Toledo B-NHL cells, the dependence of apoptosis on sustained signaling suggests that Bcl-2 family members could interpret signal duration, an important determinant of B cell receptor−mediated negative selection. Certain cases of B-NHL might respond to DAG analogue treatment by the mechanism outlined here.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2008.09.008