Foxo‐mediated <i>Bim</i> transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3‐only protein

Herold, Marco J.; Rohrbeck, Leona; Lang, Mathias Jakob; Grumont, Raelene J.; Gerondakis, Steven Demetrious; Tai, Lin; Bouillet, Philippe; Kaufmann, Thomas; Strasser, Andreas

doi:10.1038/embor.2013.152

Cited by 26 publications

(28 citation statements)

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“…46 PUMA as well as BIM expression were reported to be induced by the transcription factor FOXO3a in response to cytokine withdrawal. [47][48][49] However, mutation of all known FOXO transcription factorbinding sites in the Bim gene had no impact on haematopoietic cell homeostasis and apoptosis, 50 indicating that this mode of induction may not be critical for BIM activation. In response to ER stress, BIM expression can be transcriptionally induced by CHOP.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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“…A number of mechanisms of regulation of these Bcl-2-proteins have also been proposed, such as phosphorylation and translocation, but the only clearly established mechanism of regulation of the activity of Bcl-2-proteins is through the regulation of their levels [13]. Thus, the withdrawal of IL-2 causes some upregulation of Bim and Puma through the activity of the transcription factor Foxo3a [9], although this does not seem to be relevant for Bim-induced apoptosis [14]. Mcl-1 protein levels can be regulated through IL-7 signals [5], while Noxa is upregulated under conditions of glucose shortage [11].…”

Section: Introductionmentioning

confidence: 99%

IL‐15 regulates Bcl‐2 family members Bim and Mcl‐1 through JAK/STAT and PI3K/AKT pathways in T cells

2014

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Maintenance of T cells is determined by their survival capacity, which is regulated by IntroductionDuring maturation and in the mature state, T-cell homeostasis is regulated by two processes: apoptosis and proliferation [1,2]. In resting T cells, apoptosis is largely determined by the Bcl-2 family of proteins, and T-cell survival is regulated by the effect that extrinsic signals have on Bcl-2-family proteins [3]. The main stimuli in the regulation of both proliferation and survival are signals received by common gamma chain cytokines such as IL-7, IL-2 and IL-15, and through the TCR. The main players are similar in the regulation of apoptosis in activated T cells. At the end of the immune response, when the antigen has been cleared, most T cells Correspondence: Dr. Georg Häcker e-mail: georg.haecker@uniklinik-freiburg.de die by apoptosis. Activated T-cell death is probably mostly triggered by the disappearance of cytokines and is also mainly implemented by the Bcl-2 family of proteins, a process also referred to as mitochondrial apoptosis [1,3,4].Of the five established anti-apoptotic Bcl-2 proteins, four have been shown to be involved in the regulation of T-cell survival, namely Bcl-2, Bcl-X L , 5,6]. On the pro-apoptotic side, Bim is the most important trigger of apoptosis [7,8], while weaker activity has also been found for Puma [9,10] and during glucose deprivation for Noxa [11]. These triggers (known as BH3-only proteins) act on Bax and/or Bak, which then implement mitochondrial apoptosis [12].The main players within the apoptotic apparatus are therefore fairly well established. Substantial gaps remain, however, in our understanding how the outside signals are transduced and translated into activation or inhibition of activation of the We previously made the observation that IL-2, IL-7 and IL-15 (all cytokines signalling through the common gamma chain (γ c )), while inhibiting apoptosis in activated T cells, increase rather than decrease the protein levels of pro-apoptotic Bim [16]. In this study, we follow up on that observation and demonstrate that a similar effect is found in resting T cells. During IL-15 stimulation, both phospho-inositol-3-kinase (PI3K) and STAT signalling were necessary for the increase in Bim levels. Bim upregulation was accompanied by increased levels of Bim mRNA. A new STAT5 binding site was identified in the Bim promoter, and binding of STAT5 to this site upon IL-15 stimulation was demonstrated. Mcl-1 was further shown to be upregulated by IL-15, also requiring PI3K and STAT signalling. This suggests that the Bim upregulation is counterbalanced by Mcl-1 and may serve the function of sensitising the cells for quick apoptosis once the survival factor has disappeared. Concurrent CD3 signals also had a varying effect on the induction of Bim or Mcl-1 through γ c -signals, supporting the concept of regulation of Bcl-2 proteins through the concerted action of upstream signal transduction. Results γ c cytokines induce expression of pro-apoptotic Bim while promoting T-cell survivalWe have ...

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“…Unlike Foxo3, knockdown of Foxo1 in endothelial cells did not affect levels of Bim, 27 and while expression of constitutively active FOXO4 could induce Bim expression and apoptosis in endothelial progenitor cells, it did not induce death in mature endothelial cells. 50 Taken in combination with recent findings in hematopoietic cells, 34 it would appear that direct FOXO binding to the Bim promoter is not critical for BIM-dependent apoptosis in general. However, our analysis of endothelial apoptosis was by no means exhaustive, and we cannot exclude the possibility that …”

Section: Discussionmentioning

confidence: 78%

“…To establish whether BIM-dependent hyaloid regression was due to the redundant activity of FOXO transcription factors, we assessed hyaloid vessel regression in mice in which the four FOXO-binding sites located between positions À 625 -þ 2509 of the Bim transcriptional start site had been mutated (Bim DFoxo ). 34 Mutation of these four binding sites prevents transcriptional induction of Bim by constitutively active FOXO3. 34 Quantitative assessment at P8 showed that hyaloid regression proceeded normally in Bim DFoxo/DFoxo mice (Figure 4d).…”

Section: Resultsmentioning

confidence: 99%

“…34 Mutation of these four binding sites prevents transcriptional induction of Bim by constitutively active FOXO3. 34 Quantitative assessment at P8 showed that hyaloid regression proceeded normally in Bim DFoxo/DFoxo mice (Figure 4d). Together these results demonstrate that BIM-dependent hyaloid vessel regression proceeds independently of FOXO3, and does not require direct FOXO-dependent regulation of the Bim promoter.…”

Section: Resultsmentioning

confidence: 99%

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Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3

et al. 2014

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The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim À / À primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17B92 cluster. Bim mRNA levels were also elevated in miR-17B92 þ / À endothelial cells cultured under steady-state conditions, suggesting that miR-17B92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells.

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Foxo‐mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3‐only protein

Cited by 26 publications

References 28 publications

The BCL-2 protein family, BH3-mimetics and cancer therapy

The BCL-2 protein family, BH3-mimetics and cancer therapy

IL‐15 regulates Bcl‐2 family members Bim and Mcl‐1 through JAK/STAT and PI3K/AKT pathways in T cells

Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3

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