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Spontaneous Thymocyte Apoptosis Is Regulated by a Mitochondrion-Mediated Signaling Pathway¹

Jian Zhang^2,*,§, Katalin Mikecz^*,, Alison Finnegan^,§ and Tibor T. Glant^*,,

Section of Biochemistry and Molecular Biology, Departments of ^* Orthopedic Surgery, Biochemistry, Medicine, and ^§ Immunology/Microbiology, Rush University at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612

Most thymocytes that have not successfully rearranged their TCR genes or that express a receptor with subthreshold avidity for self-Ag/MHC enter a default apoptosis pathway, death by neglect. Spontaneous thymocyte apoptosis (STA), at least in part, may mimic this process in vitro. However, the molecular mechanism(s) by which thymocytes undergo this spontaneous apoptosis remains unknown. Here, we report that caspsase-1 and caspase-3 are activated during STA, but these caspases are dispensable for this apoptotic process. The inhibition of STA by a pan-caspase inhibitor, zVAD, suggests that multiple caspase pathways exist. Importantly, the early release of cytochrome c from mitochondria closely correlates with the degradation of Bcl-2 and Bcl-x_L and a decrease in the ratios of Bcl-2 and Bcl-x_L to Bax during STA. These findings suggest that the degradation of Bcl-2 and Bcl-x_L may favor Bax to induce cytochrome c release from mitochondria, which subsequently activates downstream caspases in STA. Our data provide the first biochemical insight into the molecular mechanism of STA.

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