Cleavage of Bax is mediated by caspase‐dependent or ‐independent calpain activation in dopaminergic neuronal cells: protective role of Bcl‐2

Abstract

Two cysteine protease families, caspase and calpain, are known to participate in cell death. We investigated whether a stress-speci®c protease activation pathway exists, and to what extent Bcl-2 plays a role in preventing drug-induced protease activity and cell death in a dopaminergic neuronal cell line, MN9D. -induced but not from STS-induced neuronal cell death. In these paradigms of dopaminergic cell death, overexpression of Bcl-2 prevented both STS-and MPP 1 -induced cell death and its associated cleavage of Bax. Thus, our results suggest that Bcl-2 may play a protective role by primarily blocking drug-induced caspase or calpain activity in dopaminergic neuronal cells.

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

“…7A), inhibited the mitochondrial translocation of Bax. This is consistent with a number of studies that determined that calpains can induce apoptosis through the activation of Bax, leading to dissipation of ΔΨ m and the release of AIF from mitochondria (38,53). In addition, both calpains and proapoptotic Bcl-2 family members are required for significant AIF release in a number of model systems (22,54).…”

MPP+ Downregulates Mitochondrially Encoded Gene Transcripts and Their Activities in Dopaminergic Neuronal Cells: Protective Role of Bcl-2

“…By contrast, several studies have suggested that Bcl-2 may also exert its anti-cell death function in nonapoptotic cell death paradigms by a less defined mechanism (17,(33)(34)(35). Recently, we have proposed that one potential protective role of Bcl-2 in nonapoptotic, caspaseindependent cell death induced by MPP ϩ resides in its anticalpain activity (29). In the present study, we raise an additional possibility that Bcl-2 may rescue energy metabolism by inhibiting MPP ϩ -induced downregulation of transcripts encoded by mitochondria thereby preserving their enzymatic functions.…”

“…5A and 5B). Although cotreatment of MN9D cells with a pancaspase inhibitor (50 -100 M BAF) substantially attenuated staurosporine-or etoposide-induced cell death by blocking caspase activity (29), cotreatment of MN9D cells with 50 -100 M BAF did not prevent MPP ϩ -induced downregulation of COX activity or a fall in the intracellular level of ATP. In conjunction with our previous reports that MPP ϩ -induced cell death is not associated with caspase activity (15,17,29), our present data implied that the protective effect of Bcl-2 on COX activity and intracellular level of ATP following MPP ϩ treatment is independent of its well-known anticaspase activity.…”

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

“…Calpains have been shown to cleave several proteins involved in apoptosis including members of the Bcl-2 family like proapoptotic members Bid and Bax, and cleavage of the prosurvival factor Bcl-xL leads to the emergence of a proapoptotic fragment. 11,[36][37][38] Pretreatment with the cellpermeable calpain inhibitor I ALLN significantly decreased the 'enhanced death' phenotype of GFP-Bfl-1 in TNFa/CHXtreated FL5.12 cells (Figure 6a), similar to proteasome inhibitor MG132 that incidentally can also suppress the activity of calpains 39 (Figure 2a; R Mellgren, personal communication). However, since ALLN is a competitive Figure 5 Mutations that interfere with efficient ubiquitination of GFP-Bfl-1 suppress its prodeath phenotype in FL5.12 cells treated with TNFa/CHX.…”