Systems biology analysis of programmed cell death

Bialik, Shani; Zalckvar, Einat; Ber, Yaara; Rubinstein, Assaf D.; Kimchi, Adi

doi:10.1016/j.tibs.2010.04.008

Trends in Biochemical Sciences

2010

DOI: 10.1016/j.tibs.2010.04.008

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Systems biology analysis of programmed cell death

Shani Bialik

Einat Zalckvar

Yaara Ber

et al.

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Cited by 86 publications

(84 citation statements)

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“…Under certain circumstances it can be causative for the programmed cellular suicide. 1,12 Furthermore, autophagy is required during periods of starvation or stress due to growth factor deprivation and therefore it has a crucial prosurvival role in cell homeostasis. 12,13 This defines the Janus role of autophagy and its ability to control a wide range of physiological processes, such as starvation, cell differentiation, cell survival, and death.…”

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“…23 Figure 1 represents some major events taking place within a cell undergoing apoptosis, or autophagy, or necroptosis and clearly shows that these three types of PCD are heavily interlinked. 1 In fact, three PCD modules are integrated into a common PCD network, where pathways of these functional modules are interconnected and where many death regulatory proteins are common to more than one module. 1 This tight control of the various PCD processes and strong connectivity of the involved proteins suggest that PCD-related proteins should possess specific (and potentially common) structural characteristics.…”

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confidence: 99%

“…1 In fact, three PCD modules are integrated into a common PCD network, where pathways of these functional modules are interconnected and where many death regulatory proteins are common to more than one module. 1 This tight control of the various PCD processes and strong connectivity of the involved proteins suggest that PCD-related proteins should possess specific (and potentially common) structural characteristics. These characteristics would allow them to be uniquely and effectively modulated via multiple specific interactions with various partners and to control the regulation and execution of different PCD modules.…”

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confidence: 99%

“…The proteins are color coded according to their intrinsic disorder content evaluated by PONDR-FIT, with highly ordered ((IDP score)o10%), moderately disordered (30%4(IDP score)410%), and highly disordered proteins ((IDP score)430%) being shown as blue, pink, and red bars, respectively. This diagram is based on the PCD maps published in 1,56,57 Protein intrinsic disorder in programmed cell death Z Peng et al…”

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Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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“…In the context of programmed cell death, key steps in apoptosis and autophagy and in the crosstalk between these pathways are regulated by protein-protein interactions and are dependent on protein complexes. 2 In a recent paper in Cell Reports, 3 we describe a programmed cell death GLuc PCA library that enables the discovery and quantitative measurement of protein-protein interactions within the cell death network. The library is based on the Gaussia luciferase protein-fragment complementation assay (PCA) reporter, which enables quantitative measurement of protein-protein interactions in a reversible manner.…”

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The programmed cell death GLuc PCA library – a powerful tool for pathway discovery and drug screening

Gilad¹,

Kimchi

2014

Molecular & Cellular Oncology

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A new function for the serine protease HtrA2 in controlling radiation‐induced senescence in cancer cells

et al. 2022

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Radiation therapy can induce cellular senescence in cancer cells, leading to short-term tumor growth arrest but increased long-term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation-induced senescence in cultured cancer cells. The irradiated cells exhibited a typical senescent phenotype, including upregulation of p53 and its main target, p21, followed by a sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescenceassociated beta-galactosidase activity. Mass spectrometry-based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy. A functional siRNA screen using a cell death-related library identified mitochondrial serine protease HtrA2 as being necessary for sustained growth arrest of the senescent cells. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus, HtrA2 is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence and the continuous maintenance of proliferation arrest.

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Systems biology analysis of programmed cell death

Cited by 86 publications

References 43 publications

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

The programmed cell death GLuc PCA library – a powerful tool for pathway discovery and drug screening

A new function for the serine protease HtrA2 in controlling radiation‐induced senescence in cancer cells

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