The biochemistry of apoptosis Hengartner, Michael O
Nature (London),
10/2000, Letnik:
407, Številka:
6805
Journal Article
Recenzirano
Apoptosis--the regulated destruction of a cell--is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its ...self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although protein expression is regulated both temporally and spatially, most proteins have an intrinsic, “typical” range of functionally effective abundance levels. These extend from a few molecules ...per cell for signaling proteins, to millions of molecules for structural proteins. When addressing fundamental questions related to protein evolution, translation and folding, but also in routine laboratory work, a simple rough estimate of the average wild type abundance of each detectable protein in an organism is often desirable. Here, we introduce a meta-resource dedicated to integrating information on absolute protein abundance levels; we place particular emphasis on deep coverage, consistent post-processing and comparability across different organisms. Publicly available experimental data are mapped onto a common namespace and, in the case of tandem mass spectrometry data, re-processed using a standardized spectral counting pipeline. By aggregating and averaging over the various samples, conditions and cell-types, the resulting integrated data set achieves increased coverage and a high dynamic range. We score and rank each contributing, individual data set by assessing its consistency against externally provided protein-network information, and demonstrate that our weighted integration exhibits more consistency than the data sets individually. The current PaxDb-release 2.1 (at http://pax-db.org/) presents whole-organism data as well as tissue-resolved data, and covers 85,000 proteins in 12 model organisms. All values can be seamlessly compared across organisms via pre-computed orthology relationships.
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related ...terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
MicroRNAs (miRNAs) are small non-coding RNAs of about 18-24 nucleotides in length that negatively regulate gene expression. Discovered only recently, it has become clear that they are involved in ...many biological processes such as developmental timing, differentiation and cell death. Data that connect miRNAs to various kinds of diseases, particularly cancer, are accumulating. miRNAs can influence cancer development in many ways, including the regulation of cell proliferation, cell transformation, and cell death. In this review, we focus on miRNAs that have been shown to play a role in the regulation of apoptosis. We first describe in detail how Drosophila has been utilized as a model organism to connect several miRNAs with the cell death machinery. We discuss the genetic approaches that led to the identification of those miRNAs and subsequent work that helped to establish their function. In the second part of the review article, we focus on the involvement of miRNAs in apoptosis regulation in mammals. Intriguingly, many of the miRNAs that regulate apoptosis have been shown to affect cancer development. In the end, we discuss a virally encoded miRNA that influences the cell death response in the mammalian host cell. In summary, the data gathered over the recent years clearly show the potential and important role of miRNAs to regulate apoptosis at various levels and in several organisms.
Fruiting body lectins are ubiquitous in higher fungi and characterized by being synthesized in the cytoplasm and up‐regulated during sexual development. The function of these lectins is unclear. A ...lack of phenotype in sexual development upon inactivation of the respective genes argues against a function in this process. We tested a series of characterized fruiting body lectins from different fungi for toxicity towards the nematode Caenorhabditis elegans, the mosquito Aedes aegypti and the amoeba Acanthamoeba castellanii. Most of the fungal lectins were found to be toxic towards at least one of the three target organisms. By altering either the fungal lectin or the glycans of the target organisms, or by including soluble carbohydrate ligands as competitors, we demonstrate that the observed toxicity is dependent on the interaction between the fungal lectins and specific glycans in the target organisms. The toxicity was found to be dose‐dependent such that low levels of lectin were no longer toxic but still led to food avoidance by C. elegans. Finally, we show, in an ecologically more relevant scenario, that challenging the vegetative mycelium of Coprinopsis cinerea with the fungal‐feeding nematode Aphelenchus avenae induces the expression of the nematotoxic fruiting body lectins CGL1 and CGL2. Based on these findings, we propose that filamentous fungi possess an inducible resistance against predators and parasites mediated by lectins that are specific for glycans of these antagonists.
Despite its apparent simplicity, the nematode worm Caenorhabditis elegans has developed into an important model for biomedical research, particularly in the functional characterization of novel drug ...targets that have been identified using genomics technologies. The cellular complexity and the conservation of disease pathways between C. elegans and higher organisms, together with the simplicity and cost-effectiveness of cultivation, make for an effective in vivo model that is amenable to whole-organism high-throughput compound screens and large-scale target validation. This review describes how C. elegans models can be used to advance our understanding of the molecular mechanisms of drug action and disease pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Research performed over the past decade has transformed apoptosis from a distinctive form of cell death known only by its characteristic morphology and genomic destruction to an increasingly well ...understood cellular disassembly pathway remarkable for its complex and multifaceted regulation. Here, we summarize current understanding of apoptotic events, note recent advances in this field and identify questions that might help guide research in the coming years.
The germline of Caenorhabditis elegans is a well-established model for DNA damage response (DDR) studies. However, the molecular basis of the observed cell death resistance in the soma of these ...animals remains unknown. We established a set of techniques to study ionizing radiation-induced DNA damage generation and DDR activation in a whole intact worm. Our single-cell analyses reveal that, although germline and somatic cells show similar levels of inflicted DNA damage, somatic cells, differently from germline cells, do not activate the crucial apical DDR kinase ataxia-telengiectasia mutated (ATM). We also show that DDR signaling proteins are undetectable in all somatic cells and this is due to transcriptional repression. However, DNA repair genes are expressed and somatic cells retain the ability to efficiently repair DNA damage. Finally, we demonstrate that germline cells, when induced to transdifferentiate into somatic cells within the gonad, lose the ability to activate ATM. Overall, these observations provide a molecular mechanism for the known, but hitherto unexplained, resistance to DNA damage-induced cell death in C. elegans somatic cells. We propose that the observed lack of signaling and cell death but retention of DNA repair functions in the soma is a Caenorhabditis-specific evolutionary-selected strategy to cope with its lack of adult somatic stem cell pools and regenerative capacity.
Ultraviolet (UV) radiation is a mutagen of major clinical importance in humans. UV-induced damage activates multiple signaling pathways, which initiate DNA repair, cell cycle arrest and apoptosis. To ...better understand these pathways, we studied the responses to UV-C light (254 nm) of germ cells in Caenorhabditis elegans. We found that UV activates the same cellular responses in worms as in mammalian cells. Both UV-induced apoptosis and cell cycle arrest were completely dependent on the p53 homolog CEP-1, the checkpoint proteins HUS-1 and CLK-2, and the checkpoint kinases CHK-2 and ATL-1 (the C. elegans homolog of ataxia telangiectasia and Rad3-related); ATM-1 (ataxia telangiectasia mutated-1) was also required, but only at low irradiation doses. Importantly, mutation of genes encoding nucleotide excision repair pathway components severely disrupted both apoptosis and cell cycle arrest, suggesting that these genes not only participate in repair, but also signal the presence of damage to downstream components of the UV response pathway that we delineate here. Our study suggests that whereas DNA damage response pathways are conserved in metazoans in their general outline, there is significant evolution in the relative importance of individual checkpoint genes in the response to specific types of DNA damage.
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