A Novel Benzodiazepine Increases the Sensitivity of B Cells to Receptor Stimulation with Synergistic Effects on Calcium Signaling and Apoptosis

Bednarski, Jeffrey J.; Lyssiotis, Costas A.; Roush, Rebecca; Boitano, Anthony E.; Glick, Gary D.; Opipari, Anthony W.

doi:10.1074/jbc.m403507200

Cited by 14 publications

(14 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cellular lysates were therefore screened with antibodies against Bad, Puma, Noxa, Bik, Bid, Bmf, and Bim. As can be seen in Figure 5A, Bz-423 does not increase the expression of any of these pro-apoptotic proteins, consistent with the inability of cycloheximide to prevent Bz-423-induced cell death [13]. In addition to increased expression, the BH3-only protein Bad can be regulated by post-translational phosphorylation of Ser-112 and Ser-136 whereby dephosphorylation triggers its activation and release from 14-3-3 proteins [14].…”

Section: Resultssupporting

confidence: 63%

See 1 more Smart Citation

Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax

Blatt

Boitano

Lyssiotis

et al. 2009

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Bz-423 is a pro-apoptotic 1,4-benzodiazepine with therapeutic properties in murine models of lupus demonstrating selectivity for autoreactive lymphocytes. Bz-423 modulates the F1F0-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. In order to understand some of the features that contribute to the increased sensitivity of lymphocytes, we report the signaling pathway engaged by Bz-423 in a Burkitt lymphoma cell line (Ramos). Following the generation of superoxide, Bz-423-induced apoptosis requires the activation of Bax and Bak to induce mitochondrial outer membrane permeabilization and cytochrome c release. Knockdown of the BH3-only proteins Bad, Bim, Bik, and Puma inhibits Bz-423 apoptosis, suggesting that these proteins serve as upstream sensors of the oxidant stress induced by Bz-423. Treatment with Bz-423 results in superoxide-dependent Mcl-1 degradation, implicating this protein as the link between Bz-423-induced superoxide and Bax and Bak activation. In contrast to fibroblasts, B cell death induced by Bz-423 is independent of c-Jun N-terminal kinase. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a specific apoptotic response that differs across cell types.

show abstract

Section: Resultssupporting

confidence: 63%

“…In MEFs Bax and Bak activation is dependent on JNK and protein synthesis, neither of which are required in Ramos cells ( vide supra and [13]). Therefore, we examined the response of upstream Bcl-2 proteins to define the mechanism that couples Bz-423-induced superoxide to Bax/Bak activation in the lymphoid cells.…”

Section: Resultsmentioning

confidence: 99%

Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax

Blatt

Boitano

Lyssiotis

et al. 2009

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since members of the MAP kinase family are differentially regulated across cell types (and stages of development) [72], the ability of a cell to activate these kinases in response to Bz-423 may be a key factor in modulating the selective response of Bz-423. Furthermore, the partial requirement for de novo protein synthesis (which follows MAP kinase activation) in the apoptotic response in MEFs helps to explain why these cells require prolonged exposure to Bz-423 relative to lymphoid cell types where Bz-423 induced death is independent of de novo protein synthesis [73]. These findings suggest that a different signal transduction pathway might link Bz-423 triggered superoxide to MOMP and apoptosis in lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax☆

Blatt

Boitano

Lyssiotis

et al. 2008

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Bz-423 is a pro-apoptotic 1,4-benzodiazepine with potent therapeutic properties in murine models of lupus and psoriasis. Bz-423 modulates the F 1 F 0 -ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. Herein, we report the signaling pathway activated by Bz-423 in mouse embryonic fibroblasts containing knockouts of key apoptotic proteins. Bz-423-induced superoxide activates cytosolic ASK1 and its release from thioredoxin. A mitogen activated protein kinase cascade follows leading to the specific phosphorylation of JNK. JNK signals activation of Bax and Bak which then induces mitochondrial outer membrane permeabilization to cause the release of cytochrome c and a commitment to apoptosis. The response of these cells to Bz-423 is critically dependent upon both superoxide and JNK activation as antioxidants and the JNK inhibitor SP600125 prevent Bax translocation, cytochrome c release, and cell death. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a sequential and specific apoptotic response. Collectively, these data suggest that the selectivity of Bz-423 observed in vivo results from cell-type specific differences in redox balance and signaling by ASK1 and Bcl-2 proteins.

show abstract

“…Diazepam has been shown to induce long lasting depression of mitogen stimulated secretion of macrophage-derived cytokines in newborn rats and production of IL-1 beta, TNF-alpha and IL-6 by monocytes isolated from peripheral blood of human patients seems to be decreased after diazepam anesthesia [20]. Most recently, a new benzodiazepine has been described capable of inducing germinal centre B-cell apoptosis, which has been suggested as a possible immunosuppressive agent in autoimmune diseases [21].…”

Section: Discussionmentioning

confidence: 98%

“Recreational” Drug Abuse Associated with Failure to Mount a Proper Antibody Response after a Generalised Orthopoxvirus Infection

et al. 2007

View full text Add to dashboard Cite

Infections with orthopoxviruses usually lead to cross-protection among all species of the family. This has been a prerequisite for successful eradication of smallpox. Here we report the rare case of a 17-year-old male, who survived a generalised cowpox virus infection of unusual severity but surprisingly did not show a proper seroconversion. Only a very weak antibody production was observed in early and late serum samples, which initially appeared to be cowpox virus specific in immunofluorescence. No neutralising antibodies were detected and in Western blotting antibody specificity was restricted to the orthopoxvirus H3L protein only. The patient had been hospitalised for alcohol and cannabis intoxication 2 months prior to the orthopoxvirus infection and high levels of cannabinoids have been found repeatedly in the urine and upon one occasion also benzodiazepines. As these substances are known to interfere with antibody production and no immunodeficiencies were detected, drug-induced immunosuppression can be suspected as the most likely cause. Therefore a possible link between "soft" drug use and sufficient immunosuppression to warrant alterations in vaccine policies using live virus vaccines like smallpox vaccine should be further studied.

show abstract

A Novel Benzodiazepine Increases the Sensitivity of B Cells to Receptor Stimulation with Synergistic Effects on Calcium Signaling and Apoptosis

Cited by 14 publications

References 44 publications

Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax

Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax

Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax☆

“Recreational” Drug Abuse Associated with Failure to Mount a Proper Antibody Response after a Generalised Orthopoxvirus Infection

Contact Info

Product

Resources

About