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

Labi, Verena; Woess, Claudia; Tuzlak, Selma; Erlacher, Miriam; Bouillet, Philippe; Strasser, Andreas; Tzankov, Alexandar

doi:10.1182/blood-2013-11-537217

Cited by 42 publications

(53 citation statements)

References 35 publications

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“…The PCR protocols for genotyping of mouse mammary tumor virus (MMTV)-Cre transgenic (line A) and WAP-Cre transgenic mice [Tg(MMTV-cre)1Mam and Tg-(Wap-cre)11738Mam, respectively] as well as the CAG-LSL-green fluorescent protein (GFP) Cre/loxP reporter strain can be found elsewhere (27)(28)(29). The generation of conventional BMF-and BIM-knockout mice as well as BMF/BIM-double-knockout mice was described earlier (30)(31)(32). All animals used in this study were treated humanely and in accordance with institutional guidelines and federal regulations.…”

Section: Methodsmentioning

confidence: 99%

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Sakamoto

Wehde

Yoo

et al. 2016

Molecular and Cellular Biology

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Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acutephase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These include Bmf and Bim, which are known regulators of programmed cell death. Using a BMF/BIMdouble-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium.T he postnatal growth, functional differentiation, and postlactational remodeling of the epithelial compartment of the mammary gland are controlled by hormones and locally synthesized cytokines (1). While estrogen is primarily required for the elongation of mammary ducts after the onset of puberty (2, 3), progesterone and prolactin orchestrate the specification, proliferation, and differentiation of secretory alveolar cells during pregnancy (4-6). Following lactation and the weaning of the young, circulating levels of prolactin (PRL) decline and milk stasis induces the local production of interleukin-6 (IL-6)-class cytokines, in particular, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM). These IL-6-class cytokines trigger a cascade of intracellular events that orchestrate a process known as mammary gland remodeling, which entails the death and selective removal of terminally differentiated alveolar cells (7-9).PRL and IL-6-class cytokines signal through their corresponding receptors and utilize Janus kinases (JAKs) to activate downstream signal transducers and activators of transcription (STATs) that subsequently alter the transcriptional profile, growth, and homeostasis of mammary epithelial cells. Five of the seven STAT proteins that are known in mammals (i.e., STAT1, STAT3, STAT5a, STAT5b, and STAT6) have been found to be sequentially activated at defined stages of mammary gland development (10, 11). The levels of phosphorylated STAT1 have been reported to be elevated in nulliparous females, but this particular transcription factor seems to be largely dispensable for normal ma...

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Section: Methodsmentioning

confidence: 99%

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Sakamoto

Wehde

Yoo

et al. 2016

Molecular and Cellular Biology

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“…Bmf −/− lymphocytes, such as pre-B cells, showed no or only minor resistance to apoptotic stimuli, but this resistance was massively increased on additional loss of even only one allele of Bim, exceeding resistance observed in Bim −/ − cells. 32 Given that Tregs require continuous TCR signalling for their maintenance and function, 33 it was surprising that we did not observe higher A1 protein levels in Tregs when compared with conventional T cells (Tcons). It has been reported that A1 mRNA levels are high in splenic Tregs but even higher in thymic Tregs when compared with the expression observed in CD4 + Tcons.…”

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confidence: 98%

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

et al. 2017

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The physiological role of the pro-survival BCL-2 family member A1 has been debated for a long time. Strong mRNA induction in T cells on T cell receptor (TCR)-engagement suggested a major role of A1 in the survival of activated T cells. However, the investigation of the physiological roles of A1 was complicated by the quadruplication of the A1 gene locus in mice, making A1 gene targeting very difficult. Here, we used the recently generated A1−/− mouse model to examine the role of A1 in T cell immunity. We confirmed rapid and strong induction of A1 protein in response to TCR/CD3 stimulation in CD4 + as well as CD8 + T cells. Surprisingly, on infection with the acute influenza HKx31 or the lymphocytic choriomeningitis virus docile strains mice lacking A1 did not show any impairment in the expansion, survival, or effector function of cytotoxic T cells. Furthermore, the ability of A1 −/− mice to generate antigen-specific memory T cells or to provide adequate CD4-dependent help to B cells was not impaired. These results suggest functional redundancy of A1 with other pro-survival BCL-2 family members in the control of T celldependent immune responses. Cell Death and Differentiation (2017) 24, 523-533; doi:10.1038/cdd.2016.155; published online 13 January 2017On antigenic challenge, T lymphocytes need to rapidly switch from their IL-7/IL-7R-regulated naive, quiescent state 1,2 to a T cell antigen-receptor (TCR/CD3) stimulation-induced activation state. 3 In case of inappropriate stimulation of the TCR, for example, in the absence of co-receptor stimulation, this shift in the survival programme is not induced and leads to rapid T cell death. 4 Conversely, appropriately stimulated T cells expand rapidly, allowing accumulation of T cell clones expressing TCRs of high affinity for specific antigens. During this clonal expansion, BCL-2 family regulated apoptosis acts as a mechanism to remove low-affinity T cells, thereby ensuring the generation of a highly effective immune response.5 On infection clearance, most of the activated T cells are removed by apoptosis, 6 leaving only some T cells with antigen-specific high-affinity TCRs in reserve as longlived memory T cells. 7The BCL-2 family of proteins regulate apoptotic cell death, with the balance between pro-survival and pro-apoptotic family members determining whether a cell lives or dies. The expression of pro-survival BCL-2 family members is dynamically regulated during T cell activation.8 TCR/CD3 ligation leads to the downregulation of BCL-2 and induction of BCL-XL.3 Accordingly, Bcl-2 −/− mice display a loss of mature, unstimulated T cells, and the death of these cells can be prevented by TCR/CD3 stimulation.9 Interestingly, although BCL-XL is substantially upregulated on TCR/CD3 stimulation, its loss did not increase apoptosis or impair proliferation of T cells stimulated with mitogenic antibodies. 10 In contrast, MCL-1 has been shown to be a crucial pro-survival factor after T cell activation.11,12 A1 is a prosurvival BCL-2 family protein that has been proposed to be i...

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“…Phenocopies Bim −/− mice regarding development; infertile males due to defective spermatogenesis (later than in Baxdeficient mice) Coultas et al 2005 Bim/Bmf Born at reduced frequency, similar to Bim −/− mice; webbed feet; increased incidence of vaginal atresia (65%) and malocclusion of the incisors (25%); increased resistance of Hubner et al 2010;Labi et al 2014;Woess et al 2015;Sakamoto et al 2016 Continued Tuzlak et al et al 2009). As a consequence, hepatocytes or pancreatic β cells from BID-deficient mice are insensitive to Fas ligation in vivo (Yin et al 1999).…”

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Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

Tuzlak

Kaufmann

2016

Genes Dev.

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“Programmed cell death or ‘apoptosis’ is critical for organogenesis during embryonic development and tissue homeostasis in the adult. Its deregulation can contribute to a broad range of human pathologies, including neurodegeneration, cancer, or autoimmunity…” These or similar phrases have become generic opening statements in many reviews and textbooks describing the physiological relevance of apoptotic cell death. However, while the role in disease has been documented beyond doubt, facilitating innovative drug discovery, we wonder whether the former is really true. What goes wrong in vertebrate development or in adult tissue when the main route to apoptotic cell death, controlled by the BCL2 family, is impaired? Such scenarios have been mimicked by deletion of one or more prodeath genes within the BCL2 family, and gene targeting studies in mice exploring the consequences have been manifold. Many of these studies were geared toward understanding the role of BCL2 family proteins and mitochondrial apoptosis in disease, whereas fewer focused in detail on their role during normal development or tissue homeostasis, perhaps also due to an irritating lack of phenotype. Looking at these studies, the relevance of classical programmed cell death by apoptosis for development appears rather limited. Together, these many studies suggest either highly selective and context-dependent contributions of mitochondrial apoptosis or significant redundancy with alternative cell death mechanisms, as summarized and discussed here.

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

Cited by 42 publications

References 35 publications

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

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