Minor cell-death defects but reduced tumor latency in mice lacking the BH3-only proteins Bad and Bmf

Baumgartner, Florian; Woess, Claudia; Pedit, V; Tzankov, Alexandar; Labi, Verena; Villunger, Andreas

doi:10.1038/onc.2012.78

Cited by 16 publications

(13 citation statements)

References 34 publications

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“…However, double deficiency failed to delay spontaneous cell death of pro-B cells in culture (data not shown), consistent with barely detectable protein expression in these cells. 19 In contrast, when pre-B cells that express significant amounts of both proteins 19 were placed in culture and apoptosis was followed over time, we noted a significant delay of death in the absence of Bim. Additional loss of Bmf further augmented this resistance to spontaneous cell death in culture, although this effect was not very pronounced ( Figure 3A).…”

Section: Bim and Bmf Coregulate B Lymphopoiesismentioning

confidence: 72%

“…This finding fits the rather poor expression of Bmf in mature T cells. 19 Notably, lymphocytes lacking For personal use only. on May 10, 2018. by guest www.bloodjournal.org From Bim and Puma do show a much broader spectrum of resistance phenotypes and are refractory to cytokine withdrawal, DNA damage, ER stress, pan-kinase inhibition, or glucocorticoid treatment.…”

Section: Discussionmentioning

confidence: 99%

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Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf

Labi

Woess

Tuzlak

et al. 2014

Blood

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Key Points• BH3-only proteins Bim and Bmf jointly coregulate developmental cell death.• Bim and Bmf act as a barrier against autoimmunity and malignant disease.BH3 domain-only proteins (BH3-only) proteins are members of the Bcl-2 family that play crucial roles in embryogenesis and the maintenance of tissue homeostasis by triggering apoptotic cell death. The BH3-only protein Bim is critical for developmental apoptosis of lymphocytes, securing establishment of tolerance and for the termination of immune responses. Bim is believed to act in concert with other BH3-only proteins or members of the tumor necrosis factor receptor family in getting rid of unwanted cells. Bmf, a related BH3-only protein, was shown to play a role in B-cell homeostasis and to mediate cell death in response to certain apoptotic triggers, including glucocorticoid, histone deacetylase inhibitors, and overexpression of the c-Myc proto-oncogene. Here we show that Bim and Bmf have overlapping functions during mouse development and coregulate lymphocyte homeostasis and apoptosis in a nonredundant manner. Double deficiency of Bim and Bmf caused more B lymphadenopathy than loss of either BH3-only protein alone, and this was associated with autoimmune glomerulonephritis and a range of malignancies in aged mice. Thus, our results demonstrate that Bim and Bmf act in concert to prevent autoimmunity and malignant disease, strengthening the rational for the development of BH3-only protein mimicking therapeutics for the treatment of such disorders. (Blood. 2014;123(17):2652-2662

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Section: Bim and Bmf Coregulate B Lymphopoiesismentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf

Labi

Woess

Tuzlak

et al. 2014

Blood

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“…). While pro‐B cells express little Mcl1, pre‐B, immature, follicular and marginal zone B cells express higher but similar levels . Similarly, most thymocyte and mature T cell subsets show comparable Mcl1 expression and the protein is also prominently expressed outside the hematopoietic compartment.…”

Section: Introductionmentioning

confidence: 99%

Lessons from gain‐ and loss‐of‐function models of pro‐survival Bcl2 family proteins: implications for targeted therapy

2015

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Cell survival depends on the maintenance of mitochondrial integrity controlled by a well-balanced interplay between anti-and pro-apoptotic B cell lymphoma 2 (Bcl2) family members. Given their frequent deregulation in human pathologies, including autoimmunity and cancer, significant research efforts have increased our molecular understanding of how Bcl2 proteins control cell death. This has fostered the development of small non-peptidic compounds, so-called BH3-mimetics, that show excellent prospects of passing clinical trials and entering daily use for targeted therapy. Possible limitations in clinical application may, to a certain degree, be predicted from loss-of-function phenotypes gathered from studies using gene-modified mice that we attempt to summarize and discuss in this context.

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“…15, 24 Studies in different cell types from bmf -deficient mice suggested, however, redundancy with other BH3-only proteins during the processes of apoptosis. 25, 26 …”

mentioning

confidence: 99%

Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death

et al. 2013

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Prolonged seizures (status epilepticus, SE) can cause neuronal death within brain regions such as the hippocampus. This may contribute to impairments in cognitive functioning and trigger or exacerbate epilepsy. Seizure-induced neuronal death is mediated, at least in part, by apoptosis-associated signaling pathways. Indeed, mice lacking certain members of the potently proapoptotic BH3-only subfamily of Bcl-2 proteins are protected against hippocampal damage caused by status epilepticus. The recently identified BH3-only protein Bcl-2–modifying factor (Bmf) normally interacts with the cytoskeleton, but upon certain cellular stresses, such as loss of extracellular matrix adhesion or energy crisis, Bmf relocalizes to mitochondria, where it can promote Bax activation and mitochondrial dysfunction. Although Bmf has been widely reported in the hematopoietic system to exert a proapoptotic effect, no studies have been undertaken in models of neurological disorders. To examine whether Bmf is important for seizure-induced neuronal death, we studied Bmf induction after prolonged seizures induced by intra-amygdala kainic acid (KA) in mice, and examined the effect of Bmf-deficiency on seizures and damage caused by SE. Seizures triggered an early (1–8 h) transcriptional activation and accumulation of Bax in the cell death-susceptible hippocampal CA3 subfield. Bmf mRNA was biphasically upregulated beginning at 1 h after SE and returning to normal by 8 h, while again being found elevated in the hippocampus of epileptic mice. Bmf upregulation was prevented by Compound C, an inhibitor of adenosine monophosphate-activated protein kinase, indicating Bmf expression may be induced in response to bioenergetic stress. Bmf-deficient mice showed normal sensitivity to the convulsant effects of KA, but, surprisingly, displayed significantly more neuronal death in the hippocampal CA1 and CA3 subfields after SE. These are the first studies investigating Bmf in a model of neurologic injury, and suggest that Bmf may protect neurons against seizure-induced neuronal death in vivo.

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Minor cell-death defects but reduced tumor latency in mice lacking the BH3-only proteins Bad and Bmf

Cited by 16 publications

References 34 publications

Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf

Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf

Lessons from gain‐ and loss‐of‐function models of pro‐survival Bcl2 family proteins: implications for targeted therapy

Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death

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