Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly ...characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Membrane structural integrity is essential for optimal mitochondrial function. These organelles produce the energy needed for all vital processes, provided their outer and inner membranes are intact. ...This prevents the release of mitochondrial apoptogenic factors into the cytosol and ensures intact mitochondrial membrane potential (ΔΨm) to sustain ATP production. Cell death by apoptosis is generally triggered by outer mitochondrial membrane permeabilization (MOMP), tightly coupled with loss of ΔΨ m. As these two processes are essential for both mitochondrial function and cell death, researchers have devised various techniques to assess them. Here, we discuss current methods and biosensors available for detecting MOMP and measuring ΔΨ m, focusing on their advantages and limitations and discuss what new imaging tools are needed to improve our knowledge of mitochondrial function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
23.
Neurotrophins and cell death Ichim, Gabriel; Tauszig-Delamasure, Servane; Mehlen, Patrick
Experimental cell research,
07/2012, Volume:
318, Issue:
11
Journal Article
Peer reviewed
The neurotrophins – NGF, BDNF, NT-3 – are secreted proteins that play a major role in neuron survival, differentiation and axon wiring toward target territories. They do so by interacting with their ...main tyrosine kinase receptors TrkA, TrkB, TrkC and p75NTR. Even though there is a general consensus on the view that neurotrophins are survival factors, there are two fundamentally different views on how they achieve this survival activity. One prevailing view is that all neurons and more generally all normal cells are naturally committed to die unless a survival factor blocks this death. This death results from the engagement of a “default” apoptotic cell program. The minority report supports, on the opposite, that neurotrophin withdrawal is associated with an active signal of cell death induced by unbound dependence receptors. We will discuss here how neurotrophins regulate cell death and survival and how this has implications not only during nervous system development but also during cancer progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Caspase-8 is involved in a number of cellular functions, with the most well established being the control of cell death. Yet caspase-8 is unique among the caspases in that it acts as an environmental ...sensor, transducing a range of signals to cells, modulating responses that extend far beyond simple survival. Ranging from the control of apoptosis and necroptosis and gene regulation to cell adhesion and migration, caspase-8 uses proteolytic and non-proteolytic functions to alter cell behavior. Novel interacting partners provide mechanisms for caspase-8 to position itself at signaling nodes that affect a variety of signaling pathways. Here, we examine the catalytic and noncatalytic modes of action by which caspase-8 influences cell adhesion and migration. The mechanisms vary from post-cleavage remodeling of the cytoskeleton to signaling elements that control focal adhesion turnover. This is facilitated by caspase-8 interaction with a host of cell proteins ranging from the proteases caspase-3 and calpain-2 to adaptor proteins such as p85 and Crk, to the Src family of tyrosine kinases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In the late eighteenth and early nineteenth centuries, in the Romanian Orthodox Church had occurred a separation between the followers of the "tradition" orthodox and those attracted to the Western ...European type of the socio-political modernization. The clerics of the first category remained attached to the idea of "Orthodox Nation" (natio as a privileged socio-national group, in the medieval sense), seeking restoration of the Byzantine Empire. The second category consisted of clergy attached to the Western European model (at the political-social level, not at the religious one), advocating for the establishment of several Balkan states, based on the democratic ideals and on the respect for citizens' rights, yet absents in that part of Europe. These clerics realized that acquiring of the national freedom of Moldavia and Wallachia is possible only through the gradual adoption of the Western political and social culture, accompanied by an armed struggle of the peoples enslaved to the Ottoman power. The followers of the Western European socio-political model had prevailed, along with the introduction, under the Russian influence, of the first modern Constitutions – the Organic Regulations – in Wallachia (July 1831) and Moldavia (January 1832). The article analyzes the institutional modernization of the Orthodox Church in Moldavia and Wallachia, under the influence of the Organic Regulations: the control of the state authority over the Church, the stipulation, by law, of the clergy’s civil and religious duties, the measures for protection of the religious buildings, the remuneration of certain categories of clergy, the establishment of the military chaplain institution. From a religious perspective, the Organic Regulations preserved the dogmas and the religious traditions of the Romanian Orthodox Church, emphasizing the subordination of the Church to the State, according to the existing model in Russia.
Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination since cancer cells can undergo partial apoptosis without dying. Recent evidence ...shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, although it remains unclear how failed apoptosis affects cancer cells. Using a cancer cell model to trigger non-lethal caspase activation, we find that melanoma cancer cells undergoing failed apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration, and modifications of the actin cytoskeleton. In line with this, cancer cells surviving apoptosis gain migration and invasion properties in vitro and in vivo. We further demonstrate that failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway, whereas its RNA sequencing signature is found in metastatic melanoma. These findings advance our understanding of how cell death can both cure and promote cancer.
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•Pro-apoptotic BH3-only proteins and chemotherapy can trigger failed apoptosis•Melanoma cells undergoing failed apoptosis are more invasive in vitro and in vivo•This pro-invasion program is regulated by JNK-AP1•The failed apoptosis gene signature can discriminate metastatic melanoma
Apoptosis is considered a complete event, efficiently killing cancer cells. Here, Berthenet et al. show that suboptimal apoptotic triggers can induce failed apoptosis, a process that enhances melanoma cancer cell aggressiveness. Moreover, failed apoptosis has a specific transcriptional signature regulated by JNK, which is enriched in metastatic melanoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The article highlights the participation of Calinic Miclescu (1822-1886), cleric of noble descent, to the main action, and political and religious decisions of Romanian modern state (1858-1885), as a ...bishop, Metropolitan of Moldova and Suceava, and Metropolitan primate of Romania. Crowning his political and religious activities was given, after a long diplomatic struggle (1878-1885), by the recognition of the Romanian Metropolitan autocephaly from the Ecumenical Patriarchate of Constantinople.
As a cellular intrinsic mechanism leading to cellular demise, apoptosis was thoroughly characterized from a mechanistic perspective. Nowadays there is an increasing interest in describing the ...non-cell autonomous or community effects of apoptosis, especially in the context of resistance to cancer treatments. Transitioning from cell-centered to cell population-relevant mechanisms adds a layer of complexity for imaging and analyzing an enormous number of apoptotic events. In addition, the community effect between apoptotic and living cells is difficult to be taken into account for complex analysis. We describe here a robust and easy to implement method to analyze the interactions between cancer cells, while under apoptotic pressure. Using this approach we showed as proof-of-concept that apoptosis is insensitive to cellular density, while the proximity to apoptotic cells increases the probability of a given cell to undergo apoptosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase ...activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.
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IJS, NUK, SBMB, UL, UM, UPUK
Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under ...conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.
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•Mitochondrial fission caused by mitochondrial dysfunction promotes DNA damage•Minority MOMP occurs on dysfunctional, fragmented mitochondria•Inter-mitochondrial heterogeneity in apoptotic priming underpins minority MOMP•BAX accumulates on dysfunctional, fragmented mitochondria, sensitizing them to MOMP
Sub-lethal apoptotic stress can cause oncogenic DNA damage. Investigating its basis, Cao, Riley, and colleagues report that mitochondrial dysfunction promotes sub-lethal apoptotic stress. Mitochondrial dysfunction causes permeabilization of select mitochondria through mitochondrial fission and pro-apoptotic BAX mitochondrial accumulation. Therefore, mitochondrial function and genome stability are interconnected via sub-lethal apoptotic stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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