A Short Mitochondrial Form of p19ARF Induces Autophagy and Caspase-Independent Cell Death

Reef, Sharon; Zalckvar, Einat; Shifman, Ohad; Bialik, Shani; Sabanay, Helena; Oren, Moshe; Kimchi, Adi

doi:10.1016/j.molcel.2006.04.014

Cited by 214 publications

(271 citation statements)

References 38 publications

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“…Assessing cell death by this assay was consistent with other more traditional and less accurate cell death assays, such as Trypan blue exclusion tests. 11 It is noted that the luminescence values are linear over several orders of magnitude, providing a wide window of detection of viable cells (between 10 2 and 10 5 cells; Supplementary Figure S4a). Moreover, every point in each experiment is tested in 10 replicates, thus conferring a high degree of Figure 1 A platform to analyze the PCD network, which combines quantitative assessment of cell death, molecular responses, and computational approaches for novel pathway discovery.…”

Section: Resultsmentioning

confidence: 99%

A systems level strategy for analyzing the cell death network: implication in exploring the apoptosis/autophagy connection

et al. 2010

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The mammalian cell death network comprises three distinct functional modules: apoptosis, autophagy and programmed necrosis. Currently, the field lacks systems level approaches to assess the extent to which the intermodular connectivity affects cell death performance. Here, we developed a platform that is based on single and double sets of RNAi-mediated perturbations targeting combinations of apoptotic and autophagic genes. The outcome of perturbations is measured both at the level of the overall cell death responses, using an unbiased quantitative reporter, and by assessing the molecular responses within the different functional modules. Epistatic analyses determine whether seemingly unrelated pairs of proteins are genetically linked. The initial running of this platform in etoposide-treated cells, using a few single and double perturbations, identified several levels of connectivity between apoptosis and autophagy. The knock down of caspase3 turned on a switch toward autophagic cell death, which requires Atg5 or Beclin-1. In addition, a reciprocal connection between these two autophagic genes and apoptosis was identified. By applying computational tools that are based on mining the protein-protein interaction database, a novel biochemical pathway connecting between Atg5 and caspase3 is suggested. Scaling up this platform into hundreds of perturbations potentially has a wide, general scope of applicability, and will provide the basis for future modeling of the cell death network. The process of programmed cell death (PCD) is driven by a network of proteins connected to each other in an intricate manner. Over the past two decades, many of the network's proteins (nodes) and the interactions among them (edges; mostly post-translation modifications) have been identified. The PCD network is turned on by well-defined input signals, such as activation of death receptors or exposure to DNA damaging agents. The efficiency of its performance determines the individual cell's probability to die, which, when assessed over a large population of cells, can be translated into the percent of cell death. Dying cells can display several distinct cell death phenotypes, each driven by a different subset of proteins and molecular pathways. Examples are the caspase-dependent apoptotic cell death, autophagic cell death and programmed necrosis. 1 Cells exposed to the same input signal can switch from one cell death modality to another in response to specific perturbations, 2-4 and in some cases, a mixed type of cell death can also be observed. [5][6][7] This led us to propose here a working model, according to which the proteins that mediate the three different cell death phenotypes should be integrated within a common network, and the corresponding subsets of proteins should be considered as functional modules within this global network. To study the network as a whole, new strategies capable of analyzing the connectivity within and between the functional modules are required.Here, we developed a platform for dissecting the network's a...

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Section: Resultsmentioning

confidence: 99%

A systems level strategy for analyzing the cell death network: implication in exploring the apoptosis/autophagy connection

et al. 2010

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“…Only a few examples are available to prove that autophagy is an important death pathway in cells with intact apoptosis machinery. 28 On the basis of several indirect evidences it has been proposed that active cell death is induced through autophagy in tamoxifen-treated MCF-7 cells; 5 one of the evidences is the inhibition of both autophagy and cell death by 3-MA, a compound that can specifically block the sequestration step in macro-autophagocytosis inhibiting class III phosphatidylinositol-kinase activity. As in our experiments 3-MA also inhibited macrophage and MCF-7 cell-mediated phagocytosis of dying de novo autophagic cells, it can be suggested that molecular events linked to autophagy and death are involved in specific surface changes, which are important in subsequent recognition and elimination of these dying cells.…”

Section: Discussionmentioning

confidence: 99%

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

et al. 2007

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MCF-7 cells undergo autophagic death upon tamoxifen treatment. Plated on non-adhesive substratum these cells died by anoikis while inducing autophagy as revealed by monodansylcadaverine staining, elevated light-chain-3 expression and electron microscopy. Both de novo and anoikis-derived autophagic dying cells were engulfed by human macrophages and MCF-7 cells. Inhibition of autophagy by 3-methyladenine abolished engulfment of cells dying through de novo autophagy, but not those dying through anoikis. Blocking exposure of phosphatidylserine (PS) on both dying cell types inhibited phagocytosis by MCF-7 but not by macrophages. Gene expression profiling showed that though both types of phagocytes expressed full repertoire of the PS recognition and signaling pathway, macrophages could evolve during engulfment of de novo autophagic cells the potential of calreticulin-mediated processes as well. Our data suggest that cells dying through autophagy and those committing anoikis with autophagy may engage in overlapping but distinct sets of clearance mechanisms in professional and non-professional phagocytes.

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“…A short form ARF, designated smARF, can be generated by internal initiation of translation. 29 This short form of ARF is translocated to the mitochondria and triggers caspaseindependent cell death. Cell death is attenuated when the expression of ATG5 and BECN1 is knocked down by siRNA.…”

Section: Cell Death (Apoptosis)mentioning

confidence: 99%

Does autophagy have a license to kill mammalian cells?

et al. 2008

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Macroautophagy is an evolutionarily conserved vacuolar, self-digesting mechanism for cellular components, which end up in the lysosomal compartment. In mammalian cells, macroautophagy is cytoprotective, and protects the cells against the accumulation of damaged organelles or protein aggregates, the loss of interaction with the extracellular matrix, and the toxicity of cancer therapies. During periods of nutrient starvation, stimulating macroautophagy provides the fuel required to maintain an active metabolism and the production of ATP. Macroautophagy can inhibit the induction of several forms of cell death, such as apoptosis and necrosis. However, it can also be part of the cascades of events that lead to cell death, either by collaborating with other cell death mechanisms or by causing cell death on its own. Loss of the regulation of bulk macroautophagy can prime selfdestruction by cells, and some forms of selective autophagy and non-canonical forms of macroautophagy have been shown to be associated with cell demise. There is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell survival and cell death. The term 'autophagy' embraces several different mechanisms: microautophagy, macroautophagy and chaperone-mediated autophagy, 1 all of which are involved in the lysosomal degradation of cellular components. In this review, we will focus essentially on macroautophagy, because of the large body of data available about its cross talk with cell death. Macroautophagy (hereafter called 'autophagy') is a mechanism conserved among eukaryotic cells that starts with the formation of a multi-membrane-bound vacuole, known as an autophagosome, which ultimately fuses with the lysosomal compartment and the degradation of the sequestered material. 2 The seminal discovery of autophagy-related (ATG) genes initially in yeast and then in multicellular organisms 3,4 has led to an important breakthrough in the understanding of how autophagosomes are formed and of the part autophagy plays in cell physiology and human diseases. 1,5 To clarify how macroautophagy is modulated in response to stress situations, it is also absolutely essential to elucidate how the macroautophagy is regulated upstream of the Atg machinery. 6 Macroautophagy occurs at a basal rate in most cells, where it acts as a cytoplasmic quality-control mechanism to eliminate protein aggregates and damaged organelles. 1,5 The physiological importance of basal autophagy in maintaining tissue homeostasis has recently been demonstrated in conditional brain and liver Atg knockout mouse models. [7][8][9] These studies have demonstrated the role of autophagy in preventing the cytotoxic deposition of aggregate-prone proteins in the cytoplasm, and the contribution of autophagy to the elimination of ubiquitinated proteins that are efficient substrates for the proteasome.On the other hand, when the supply of nutrients is limited, starvation-induced autophagy contrib...

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A Short Mitochondrial Form of p19ARF Induces Autophagy and Caspase-Independent Cell Death

Cited by 214 publications

References 38 publications

A systems level strategy for analyzing the cell death network: implication in exploring the apoptosis/autophagy connection

A systems level strategy for analyzing the cell death network: implication in exploring the apoptosis/autophagy connection

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

Does autophagy have a license to kill mammalian cells?

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