Elucidation of Anti-Proliferative and Pro-Apoptotic Signaling Induced by the Immunomodulatory Benzodiazepine Bz-423.

Mitochondrial FoF1-ATPase;Lupus;T Cell Apoptosis;Myc;Reactive Oxygen Species Signaling;Noxa;Biological Chemistry;Science;Chemistry

Sundberg, Thomas B.Marsh, E Neil G. ;

University of Michigan

关键词: Mitochondrial FoF1-ATPase;    Lupus;    T Cell Apoptosis;    Myc;    Reactive Oxygen Species Signaling;    Noxa;    Biological Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/62392/tsundber_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Bz-423 is a non-anxiolytic 1,4-benzodiazepine that ameliorates disease in animal models of lupus, arthritis and psoriasis.Concomitant with these therapeutic effects, Bz-423 induces lineage-specific apoptosis of pathogenic lymphocytes or selectively blocks proliferation of psoriatic skin cells.Mechanistic studies in B cells demonstrated that Bz-423 promotes mitochondrial superoxide (O2•–) production, and the magnitude of this response distinguishes between growth arrest and apoptosis.The Bz-423 induced O2•– response results from modulation of the FoF1-ATPase.Bz-423 binds to the oligomycin sensitivity-conferring protein (OSCP) component of the FoF1-ATPase, which causes the rate of ATP synthesis to slow and forces the mitochondrial respiratory chain into a reduced state that favors overproduction of O2•–.The overarching goal of the experiments described in this dissertation is, therefore, to identify factors underlying the selective effects of Bz-423 on pathogenic cells in vivo by elucidating signaling pathways that link elevated mitochondrial O2•– production to growth arrest or apoptosis.Towards this goal, proteasomal degradation of c-Myc, an oncogenic transcription factor that regulates cell-cycle progression, was identified as an essential component of the mechanism leading to Bz-423 induced growth arrest.While this mechanism was identified in B cells, it likely contributes to the anti-psoriatic activity because c-Myc levels are reduced in psoriatic skin treated with Bz-423. Although Bz-423 specifically depletes pathogenic CD4+ T cells in the MRL/MpJ-Faslpr murine model of lupus, the apoptotic response to Bz-423 has been characterized primarily in B cells.To address this point, Bz-423-induced apoptosis was investigated in CD4+ T cell leukemia lines.Unlike some pro-oxidants, Bz-423 induced O2•– does not cause opening of the mitochondrial permeability transition pore, but instead triggers a specific, extra-mitochondrial cascade marked by increased levels of the pro-apoptototic Bcl-2 family proteins Noxa and Bak.The resulting activation of Bak, commits a cell to die in response to Bz-423 by inducing release of apoptogenic proteins (e.g., cytochrome c) sequestered inside mitochondria.Intersection of this apoptotic mechanism with vulnerabilities in autoreactive T cells, including mitochondrial bioenergetic abnormalities favoring overproduction O2•– and upregulation of Noxa in response to antigenic stimulation, likely underlies the selective depletion of pathogenic lymphocytes in vivo.