Abstract:
BACKGROUND:Autophagy mediates lysosomal degradation of cytosolic components. Recent work has associated autophagic dysfunction with pathologies, including cancer and cardiovascular disease. To date, the identification of clinically-applicable drugs that modulate autophagy has been hampered by the lack of standardized assays capable of precisely reporting autophagic activity. RESULTS:We developed and implemented a high-content, flow-cytometry-based screening approach for rapid, precise, and quantitative measurements of pharmaceutical control over autophagy. Our assay allowed for time-resolved individual measurements of autolysosome formation and degradation, and endolysosomal activities under both basal and activated autophagy conditions. As proof of concept, we analyzed conventional autophagy regulators, including cardioprotective compounds aminoimidazole carboxamide ribonucleotide (AICAR), rapamycin, and resveratrol, and revealed striking conditional dependencies of rapamycin and autophagy inhibitor 3-methyladenine (3-MA). To identify novel autophagy modulators with translational potential, we screened the Prestwick Chemical Library of 1,120 US Food and Drug Administration (FDA)-approved compounds for impact on autolysosome formation. In all, 38 compounds were identified as potential activators, and 36 as potential inhibitors of autophagy. Notably, amongst the autophagy enhancers were cardiac glycosides, from which we selected digoxin, strophanthidin, and digoxigenin for validation by standard biochemical and imaging techniques. We report the induction of autophagic flux by these cardiac glycosides, and the concentrations allowing for specific enhancement of autophagic activities without impact on endolysosomal activities. CONCLUSIONS:Our systematic analysis of autophagic and endolysosomal activities outperformed conventional autophagy assays and highlights the complexity of drug influence on autophagy. We demonstrate conditional dependencies of established regulators. Moreover, we identified new autophagy regulators and characterized cardiac glycosides as novel potent inducers of autophagic flux.
journal_name
BMC Bioljournal_title
BMC biologyauthors
Hundeshagen P,Hamacher-Brady A,Eils R,Brady NRdoi
10.1186/1741-7007-9-38subject
Has Abstractpub_date
2011-06-02 00:00:00pages
38issn
1741-7007pii
1741-7007-9-38journal_volume
9pub_type
杂志文章相关文献
BMC BIOLOGY文献大全abstract:BACKGROUND:TPA Induced Sequence 7 acts as a transcriptional co-regulator controlling the expression of genes involved in differentiation of various cell types, including skeletal myoblasts. We and others have shown that TIS7 regulates adult myogenesis through MyoD, one of the essential myogenic regulatory factors. RES...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-016-0318-6
更新日期:2016-10-25 00:00:00
abstract:BACKGROUND:The availability of abundant sequence data from key model organisms has made large scale studies of molecular evolution an exciting possibility. Here we use full length cDNA alignments comprising more than 700,000 nucleotides from human, mouse, pig and the Japanese pufferfish Fugu rubrices in order to invest...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-3-2
更新日期:2005-01-28 00:00:00
abstract:BACKGROUND:Early developmental patterns of flatworms are extremely diverse and difficult to compare between distant groups. In parasitic flatworms, such as tapeworms, this is confounded by highly derived life cycles involving indirect development, and even the true orientation of the tapeworm antero-posterior (AP) axis...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-016-0233-x
更新日期:2016-03-04 00:00:00
abstract::A recent paper published in BMC Genomics suggests that retrotransposition may be active in the human gut parasite Entamoeba histolytica. This adds to our knowledge of the various types of repetitive elements in parasitic protists and the potential influence of such elements on pathogenicity. ...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-8-64
更新日期:2010-05-24 00:00:00
abstract:BACKGROUND:Signaling by the Wnt family of secreted glycoproteins through their receptors, the frizzled (Fz) family of seven-pass transmembrane proteins, is critical for numerous cell fate and tissue polarity decisions during development. RESULTS:We report a novel role of Wnt signaling in organogenesis using the format...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-3-23
更新日期:2005-10-24 00:00:00
abstract::Joel Dacks is an Associate Professor and Canada Research Chair in Evolutionary Cell Biology at the University of Alberta, a Scientific Associate at the Natural History Museum (London), and the current President of the International Society for Evolutionary Protistology. His research group studies the evolution and div...
journal_title:BMC biology
pub_type: 传,历史文章,面试
doi:10.1186/s12915-018-0586-4
更新日期:2018-11-01 00:00:00
abstract:BACKGROUND:Methods for assigning strains to bacterial species are cumbersome and no longer fit for purpose. The concatenated sequences of multiple house-keeping genes have been shown to be able to define and circumscribe bacterial species as sequence clusters. The advantage of this approach (multilocus sequence analysi...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-7-3
更新日期:2009-01-26 00:00:00
abstract::Exosomes are extracellular vesicles first described as such 30 years ago and since implicated in cell-cell communication and the transmission of disease states, and explored as a means of drug discovery. Yet fundamental questions about their biology remain unanswered. Here I explore what exosomes are, highlight the di...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-016-0268-z
更新日期:2016-06-13 00:00:00
abstract:BACKGROUND:Increasing evidence suggests that influenza reassortment not only contributes to the emergence of new human pandemics but also plays an important role in seasonal influenza epidemics, disease severity, evolution, and vaccine efficacy. We studied this process within 2091 H3N2 full genomes utilizing a combinat...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-016-0337-3
更新日期:2016-12-29 00:00:00
abstract::The vertebrate nervous system is deeply divided into 'somatic' and 'visceral' subsystems that respond to external and internal stimuli, respectively. Molecular characterization of neurons in different groups of mollusks by Nomaksteinsky and colleagues, published in this issue of BMC Biology, reveals that the viscero-s...
journal_title:BMC biology
pub_type: 评论,杂志文章
doi:10.1186/1741-7007-11-54
更新日期:2013-04-30 00:00:00
abstract:BACKGROUND:Mate choice is of central importance to most animals, influencing population structure, speciation, and ultimately the survival of a species. Mating behavior of male brachionid rotifers is triggered by the product of a chemosensory gene, a glycoprotein on the body surface of females called the mate recogniti...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-7-60
更新日期:2009-09-09 00:00:00
abstract:BACKGROUND:Nucleolar rDNA is tightly associated with silent heterochromatin, which is important for rDNA stability, nucleolar integration, and cellular senescence. Two pathways have been described that lead to rDNA silencing in yeast: 1) the RENT (regulator of nucleolar silencing and telophase exit) complex, which is c...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-014-0075-3
更新日期:2014-09-24 00:00:00
abstract:BACKGROUND:Dinoflagellates are taxonomically diverse and ecologically important phytoplankton that are ubiquitously present in marine and freshwater environments. Mostly photosynthetic, dinoflagellates provide the basis of aquatic primary production; most taxa are free-living, while some can form symbiotic and parasiti...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-020-00782-8
更新日期:2020-05-24 00:00:00
abstract:BACKGROUND:Internal tagging of proteins by inserting small functional peptides into surface accessible permissive sites has proven to be an indispensable tool for basic and applied science. Permissive sites are typically identified by transposon mutagenesis on a case-by-case basis, limiting scalability and their exploi...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-017-0440-0
更新日期:2017-10-30 00:00:00
abstract::The close association between hematopoietic and endothelial cells during embryonic development led to the proposal that they may originate from a common ancestor--the hemangioblast. Due to a lack of unique specific markers for in vivo cell fate tracking studies, evidence supporting this theory derives mainly from in v...
journal_title:BMC biology
pub_type: 社论
doi:10.1186/1741-7007-9-88
更新日期:2011-12-28 00:00:00
abstract:BACKGROUND:Invariant natural killer T (iNKT) cells differ from other T cells by their hyperactive effector T-cell status, in addition to the expression of NK lineage receptors and semi-invariant T-cell receptors. It is generally agreed that the immune phenotype of iNKT cells is maintained by repeated activation in peri...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-8-142
更新日期:2010-11-30 00:00:00
abstract:BACKGROUND:ADP-ribosylation is a ubiquitous post-translational modification that involves both mono- and poly-ADP-ribosylation. ARTD10, also known as PARP10, mediates mono-ADP-ribosylation (MARylation) of substrate proteins. A previous screen identified protein kinase C delta (PKCδ) as a potential ARTD10 substrate, amo...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-020-00878-1
更新日期:2020-10-15 00:00:00
abstract::There are many reasons to be interested in stem cells, one of the most prominent being their potential use in finding better drugs to treat human disease. This article focuses on how this may be implemented. Recent advances in the production of reprogrammed adult cells and their regulated differentiation to disease-re...
journal_title:BMC biology
pub_type: 杂志文章,评审
doi:10.1186/1741-7007-9-42
更新日期:2011-06-07 00:00:00
abstract:BACKGROUND:O-fucosyltransferase1 (OFUT1) is a conserved ER protein essential for Notch signaling. OFUT1 glycosylates EGF domains, which can then be further modified by the N-acetylglucosaminyltransferase Fringe. OFUT1 also possesses a chaperone activity that promotes the folding and secretion of Notch. Here, we investi...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-6-1
更新日期:2008-01-14 00:00:00
abstract:BACKGROUND:Marine molluscs, as is the case with most aquatic animals, rely heavily on olfactory cues for survival. In the mollusc Aplysia californica, mate-attraction is mediated by a blend of water-borne protein pheromones that are detected by sensory structures called rhinophores. The expression of G protein and phos...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-7-28
更新日期:2009-06-04 00:00:00
abstract::Huntington's disease (HD) is one of the most common tandem repeat disorders and presents as a unique trilogy of cognitive, psychiatric and motor symptoms. One of the major mysteries of HD is why it selectively affects specific neuronal populations. A new article in BMC Biology provides a piece in the puzzle of pathoge...
journal_title:BMC biology
pub_type: 评论,杂志文章
doi:10.1186/s12915-018-0539-y
更新日期:2018-06-27 00:00:00
abstract:BACKGROUND:Within chromatin, the histone variant H2A.Z plays a role in many diverse nuclear processes including transcription, preventing the spread of heterochromatin and epigenetic transcriptional memory. The molecular mechanisms of how H2A.Z mediates its effects are not entirely understood. However, it is now known ...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-7-86
更新日期:2009-12-14 00:00:00
abstract:BACKGROUND:Thiazolidinediones are antidiabetic agents that increase insulin sensitivity but reduce glucose oxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain (MRC). The mechanisms of the latter effects are unclear. The aim of this study was to determine the mechanisms by wh...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-11-88
更新日期:2013-08-01 00:00:00
abstract::The circadian clock enhances fitness through temporal organization of plant gene expression, metabolism and physiology. Two recent studies, one in BMC Evolutionary Biology, demonstrate through phylogenetic analysis of the CCA1/LHY and TOC1/PRR gene families that the common ancestor of monocots and eudicots had compone...
journal_title:BMC biology
pub_type: 评论,杂志文章,评审
doi:10.1186/1741-7007-8-55
更新日期:2010-05-07 00:00:00
abstract:BACKGROUND:Regulatory T cells (Tregs) expressing the transcription factor FOXP3 are crucial mediators of self-tolerance, preventing autoimmune diseases but possibly hampering tumor rejection. Clinical manipulation of Tregs is of great interest, and first-in-man trials of Treg transfer have achieved promising outcomes. ...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-018-0518-3
更新日期:2018-05-07 00:00:00
abstract:BACKGROUND:Kinases mTORC1 and AMPK act as energy sensors, controlling nutrient responses and cellular growth. Changes in nutrient levels affect diverse transcriptional networks, making it challenging to identify downstream paths that regulate cellular growth or a switch to development via nutrient variation. The life c...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/s12915-019-0673-1
更新日期:2019-07-18 00:00:00
abstract:BACKGROUND:A key event in plant morphogenesis is the establishment of a division plane. A plant-specific microtubular preprophase band (PPB) accurately predicts the line of cell division, whereas the phragmoplast, another plant-specific array, executes cell division by maintaining this predicted line. Although establis...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-3-11
更新日期:2005-04-14 00:00:00
abstract:BACKGROUND:The ParaHox gene cluster is the evolutionary sister to the Hox cluster. Whilst the role of the Hox cluster in patterning the anterior-posterior axis of bilaterian animals is well established, and the organisation of vertebrate Hox clusters is intimately linked to gene regulation, much less is known about the...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-7-43
更新日期:2009-07-23 00:00:00
abstract:BACKGROUND:Whole genome duplication (WGD) is a special case of gene duplication, observed rarely in animals, whereby all genes duplicate simultaneously through polyploidisation. Two rounds of WGD (2R-WGD) occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis ...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-8-146
更新日期:2010-12-13 00:00:00
abstract:BACKGROUND:A new family of natural products has been described in which cysteine, serine and threonine from ribosomally-produced peptides are converted to thiazoles, oxazoles and methyloxazoles, respectively. These metabolites and their biosynthetic gene clusters are now referred to as thiazole/oxazole-modified microci...
journal_title:BMC biology
pub_type: 杂志文章
doi:10.1186/1741-7007-8-70
更新日期:2010-05-25 00:00:00