Disease relevance of Bcl2l11

• The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia [1].
• Our results suggest that following preconditioning ischemia, Bim is rapidly degraded by the ubiquitin-proteasome system, resulting in rapid ischemic tolerance [2].
• We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy [3].

High impact information on Bcl2l11

• Addition of a peptide corresponding to the BH3 domain of the proapoptotic protein Bim to cell lysates triggered a similar conformational change in Bcl-2, demonstrating that preexisting, membrane-bound Bcl-2 proteins change topology [4].
• A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim [3].
• Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy [3].
• In healthy cells, Bcl-w was loosely attached to the mitochondrial membrane, but it was converted into an integral membrane protein by cytotoxic signals that induce binding of BH3-only proteins, such as Bim, or by the addition of BH3 peptides to lysates [5].
• Bim, the Bcl-2 interacting mediator of cell death, is a member of the BH3-only family of pro-apoptotic proteins [6].

Biological context of Bcl2l11

• These results indicate that Rac acts downstream of integrins and growth factors to promote neuronal survival by repressing c-Jun/Bim-mediated mitochondrial apoptosis [7].
• Thus, NGF protects neurons from the proapoptotic effects of Bim both by acute phosphorylation and the longer term repression of expression [8].
• We report here that nerve growth factor (NGF) leads to both a slow down-regulation of Bim expression in neuronal PC12 cells and rapid Bim phosphorylation [8].
• The Bim promoter contains two myb binding sites, mutation of which abolishes induction of a Bim promoter-driven reporter by NGF deprivation or E2F-dependent gene de-repression [9].
• In contrast to the situation in trophic factor-deprived neurons, no up-regulation of Bim or Harakiri/DP5 proteins occurred after kainic acid, suggesting alternative pathways for regulation of cell death in excitotoxicity [10].

Anatomical context of Bcl2l11

• These results suggest that the JNK signaling pathway is involved in ischemia-induced neuronal apoptosis by stimulation, at least in part, of Bax translocation to the mitochondria, in which BimL is likely regulated by JNK as a downstream substrate for transmission of apoptotic signals to Bax [1].
• In this report, we investigated the signaling pathways leading to Bim phosphorylation in Ba/F3 cells, an interleukin-3 (IL-3)-dependent B-cell line [6].
• The relative levels of Bim mRNA in retina were significantly higher 4 days after optic nerve transection and below normal levels at 14 days after transection [11].

Associations of Bcl2l11 with chemical compounds

• ToxB stimulated mitochondrial translocation and conformational activation of Bax, c-Jun activation, and induction of the BH3-only protein Bim [7].
• A c-jun N-terminal protein kinase (JNK)/p38 inhibitor, SB203580, and a JNK-specific inhibitor, SP600125, significantly decreased ToxB-induced Bim expression and blunted each subsequent step of the apoptotic cascade [7].
• High glucose sequentially increases the expression, activation and localization of the pro-apoptotic proteins Bim and Bax and the mitochondrial fission protein dynamin-regulated protein 1 (Drp1) [12].
• In contrast, chronic exposure to MG-132 increased the expression and phosphorylation of c-Jun, elevated levels of the pro-apoptotic protein Bim, and triggered neuronal apoptosis, even in the presence of depolarizing medium [13].

Physical interactions of Bcl2l11

• Here, we show that the pro-apoptotic Bcl-2 homology 3 domain-only molecule Bcl-2 interacting mediator of cell death (Bim) is a target of a cell-cycle-related apoptotic pathway in neuronal cells [9].

Regulatory relationships of Bcl2l11

• Moreover, ToxB rapidly suppressed a p21-activated kinase/MAP kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling cascade that normally promotes degradation of the Bcl-2 homology-3 (BH3)-only protein Bim, a key initiator of mitochondrial apoptosis [14].
• Bim is classically thought to promote apoptosis by neutralizing pro-survival Bcl-2 proteins [15].

Other interactions of Bcl2l11

• Binding motifs were then minimized to seven or eight amino acid long peptides: YSKETQT for dynein IC, CDKSTQT for Bim, KDTGIQVD for nNOS, QSVGVQV for DAP1alpha and EDKNTMTD for myosin V [16].
• Bim is a proapoptotic, BH3-domain-only member of the Bcl-2 family that plays a role in death of trophic factor-deprived sympathetic neurons as well as in other paradigms of apoptotic death [8].
• Induction of both proapoptotic (Bcl2l11, Casp6) and antiapoptotic (Bcl-X) genes, besides suppression of p21, suggest complex cell death/protection-related mechanisms operating early on [17].
• Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim [18].
• Within 1 h after SCI in rats, DP5 was induced, while Bim and Bad levels remained unchanged [19].

Analytical, diagnostic and therapeutic context of Bcl2l11

• IL-3 stimulation induced phosphorylation of Bim(EL), one of the predominant isoforms of Bim expressed in cells, at multiple sites, as evidenced by the formation of at least three to four bands by Western blotting that were sensitive to phosphatase digestion [6].
• To study the involvement of Bim in injury-induced cell death in retina, Bim expression was studied in normal rat retina and in retina after optic nerve transection using quantitative RT-PCR and immunohistochemistry [11].

References