共查询到20条相似文献,搜索用时 31 毫秒
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Alexandra E. Goetz Miles Wilkinson 《Cellular and molecular life sciences : CMLS》2017,74(19):3509-3531
Cells respond to internal and external cellular stressors by activating stress-response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—nonsense-mediated RNA decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting that it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses. 相似文献
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Yuan J Dong Z Guo JP McGeehan J Xiao X Wang J Cali I McGeer PL Cashman NR Bessen R Surewicz WK Kneale G Petersen RB Gambetti P Zou WQ 《Cellular and molecular life sciences : CMLS》2008,65(4):631-643
Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated
PrP27 – 30 detectable by the 3F4 antibody against human PrP109 – 112. We recently identified a new PK-resistant PrP species,
designated PrP*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 – 108 but
not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility
of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic
mutant PrP accumulate not only PrP*20 but also a small amount of 3F4-detected PK-resistant PrP27 – 30. Remarkably, during the course of human prion disease, a
transition from an increase in 1E4-detected PrP*20 to the occurrence of the 3F4-detected PrP27 – 30 was observed. Our study suggests that an increase in the level of PrP*20 characterizes the early stages of prion diseases.
Received 17 October 2007; received after revision 5 December 2007; accepted 14 December 2007 相似文献
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Ca2+ influx evoked across the plasma membrane upon internal store depletion is essential for a myriad of cellular functions including
gene expression, cell proliferation, differentiation and even apoptosis. Darier’s disease (DD), an autosomal dominant inherited
disorder of the skin, arising due to mutations in the isoform 2 of the sarco (endo) plasmic reticulum Ca2+ ATPase (SERCA2), exemplifies an anomaly of Ca2+ signaling disturbances. Owing to loss of function mutations in SERCA2, keratinocytes in DD patients have a reduced pool of
endoplasmic reticulum (ER) Ca2+. Importantly, the status of ER Ca2+ is critical for the activation of a class of plasma membrane Ca2+ channels referred to as store operated Ca2+ channels (SOCs). The widely expressed transient receptor potential (TRP) family of channels is proposed to be SOCs. In this
review we discuss DD from the viewpoint of Ca2+ signaling and present a potential role for TRPC1 in the disease pathogenesis.
Received 30 August 2007; received after revision 17 October 2007; accepted 6 November 2007 相似文献
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Kaser A Niederreiter L Blumberg RS 《Cellular and molecular life sciences : CMLS》2011,68(22):3643-3649
The intestinal epithelium forms a highly active functional interface between the relatively sterile internal body surfaces
and the enormously complex and diverse microbiota that are contained within the lumen. Genetic models that allow for manipulation
of genes specifically in the intestinal epithelium have provided an avenue to understand the diverse set of pathways whereby
intestinal epithelial cells (IECs) direct the immune state of the mucosa associated with homeostasis versus either productive
or non-productive inflammation as occurs during enteropathogen invasion or inflammatory bowel disease (IBD), respectively.
These pathways include the unfolded protein response (UPR) induced by stress in the endoplasmic reticulum (ER), autophagy,
a self-cannibalistic pathway important for intracellular bacterial killing and proper Paneth cell function as well as the
interrelated functions of NOD2/NF-κB signaling which also regulate autophagy induction. Multiple genes controlling these IEC
pathways have been shown to be genetic risk factors for human IBD. This highlights the importance of these pathways not only
for proper IEC function but also suggesting that IECs may be one of the cellular originators of organ-specific and systemic
inflammation as in IBD. 相似文献
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Calorie restriction and the nutrient sensing signaling pathways 总被引:3,自引:0,他引:3
Calorie restriction (CR) is the most potent regimen known to extend the life span in multiple species. CR has also been shown
to ameliorate several age-associated disorders in mammals and perhaps humans. CR induces diverse metabolic changes in organisms,
and it is currently unclear whether and how these metabolic changes lead to life span extension. Recent studies in model systems
have provided insight into the molecular mechanisms by which CR extends life span. In this review, we summarize and provide
recent updates on multiple nutrient signaling pathways that have been connected to CR and longevity regulation. The roles
of highly conserved longevity regulators – the Sirtuin family – in CR are also discussed.
Received 25 August 2006; received after revision 9 October 2006; accepted 13 December 2006 相似文献
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Viero G Gropuzzo A Joubert O Keller D Prévost G Dalla Serra M 《Cellular and molecular life sciences : CMLS》2008,65(2):312-323
γ-Hemolysins are pore-forming toxins which develop from water-soluble monomers by combining two different ‘albeit homologous’
proteins. They form oligomeric pores in both cell and model membranes by undergoing a still poorly understood conformational
rearrangement in the stem region. The stem is formed by three β-strands, folded onto the core of the soluble protein and completely
extended in the pore. We propose a new model to explain such a process. Seven double-cysteine mutants were developed by inserting
one cysteine on the stretch that links the β-hairpin to the core of the protein and another on different positions along the
β-strands. The membrane bound protein was blocked in a non-lytic state by S–S bond formation. Six mutants were oxidized as
inactive intermediates, but became active after adding DTT. These results demonstrate that the stem extension can be temporarily
frozen and that the β-barrel formation occurs by β-strand concerted step-by-step sliding.
Received 22 October 2007; received after revision 15 November 2007; accepted 19 November 2007 相似文献
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The annexins: spatial and temporal coordination of signaling events during cellular stress 总被引:2,自引:0,他引:2
Katia Monastyrskaya Eduard B. Babiychuk Annette Draeger 《Cellular and molecular life sciences : CMLS》2009,66(16):2623-2642
Annexins are a family of structurally related, Ca2+-sensitive proteins that bind to negatively charged phospholipids and establish specific interactions with other lipids and
lipid microdomains. They are present in all eukaryotic cells and share a common folding motif, the “annexin core”, which incorporates
Ca2+- and membrane-binding sites. Annexins participate in a variety of intracellular processes, ranging from the regulation of
membrane dynamics to cell migration, proliferation, and apoptosis. Here we focus on the role of annexins in cellular signaling
during stress. A chronic stress response triggers the activation of different intracellular pathways, resulting in profound
changes in Ca2+ and pH homeostasis and the production of lipid second messengers. We review the latest data on how these changes are sensed
by the annexins, which have the ability to simultaneously interact with specific lipid and protein moieties at the plasma
membrane, contributing to stress adaptation via regulation of various signaling pathways. 相似文献
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G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
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The polypyrimidine tract binding protein (PTB) is a 58-kDa RNA binding protein involved in multiple aspects of mRNA metabolism
including splicing regulation, polyadenylation, 3′end formation, internal ribosomal entry site-mediated translation, RNA localization
and stability. PTB contains four RNA recognition motifs (RRMs) separated by three linkers. In this review we summarize structural
information on PTB in solution that has been gathered during the past 7 years using NMR spectroscopy and small-angle X-ray
scattering. The structures of all RRMs of PTB in their free state and in complex with short pyrimidine tracts, as well as
a structural model of PTB RRM2 in complex with a peptide, revealed unusual structural features that provided new insights
into the mechanisms of action of PTB in the different processes of RNA metabolism and in particular splicing regulation.
Received 16 August 2007; received after revision 18 September 2007; accepted 2 October 2007 相似文献
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The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis, and is implicated
in human disease. Wnts transduce signals via transmembrane receptors of the Frizzled (Fzd/Fz) family and the low density lipoprotein
receptor-related protein 5/6 (Lrp5/6). A key mechanism in their signal transduction is that Wnts induce Lrp6 signalosomes,
which become phosphorylated at multiple conserved sites, notably at PPSPXS motifs. Lrp6 phosphorylation is crucial to β-catenin
stabilization and pathway activation by promoting Axin and Gsk3 recruitment to phosphorylated sites. Here, we summarize how
proline-directed kinases (Gsk3, PKA, Pftk1, Grk5/6) and non-proline-directed kinases (CK1 family) act upon Lrp6, how the phosphorylation
is regulated by ligand binding and mitosis, and how Lrp6 phosphorylation leads to β-catenin stabilization. 相似文献
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AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism 总被引:1,自引:0,他引:1
Witczak CA Sharoff CG Goodyear LJ 《Cellular and molecular life sciences : CMLS》2008,65(23):3737-3755
The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator
of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this
review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include
the following: (1) the structural components of the three AMPK subunits (i.e. AMPKα, β, and γ), and their differential localization
in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known
upstream kinases, LKB1, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-β-activated kinase 1 (TAK1); (3) the pharmacological
agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate
AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle.
Received 04 May 2008; received after revision 14 June 2008; accepted 14 July 2008 相似文献
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D. Parolini M. Meregalli M. Belicchi P. Razini R. Lopa B. Del Carlo A. Farini S. Maciotta N. Bresolin L. Porretti M. Pellegrino Y. Torrente 《Cellular and molecular life sciences : CMLS》2009,66(4):697-710
Among the heterogeneous population of circulating hematopoietic and endothelial progenitors, we identified a subpopulation
of CD133+ cells displaying myogenic properties. Unexpectedly, we observed the expression of the B-cell marker CD20 in blood-derived
CD133+ stem cells. The CD20 antigen plays a role in the modulation of intracellular calcium homeostasis through signaling pathways
activation. Several observations suggest that an increase in intracellular calcium concentration ([Ca2+]i) could be involved in the etiology of the Duchenne muscular dystrophy (DMD). Here, we show that a CD20-related signaling
pathway able to induce an increase in [Ca2+]i is differently activated after brain derived neurotrophic factor (BDNF) stimulation of normal and dystrophic blood-derived
CD133+ stem cells, supporting the assumption of a “CD20-related calcium impairment-affecting dystrophic cells. Presented findings
represent the starting point toward the expansion of knowledge on pathways involved in the pathology of DMD and in the behavior
of dystrophic blood-derived CD133+ stem cells.
Received 15 October 2008; received after revision 27 November 2008; accepted 05 December 2008 相似文献
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SongTing Shi David J. J. de Gorter Willem M. H. Hoogaars Peter A. C. ’t Hoen Peter ten Dijke 《Cellular and molecular life sciences : CMLS》2013,70(3):407-423
Bone morphogenetic proteins (BMPs) are important extracellular cytokines that play critical roles in embryogenesis and tissue homeostasis. BMPs signal via transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad effector proteins. BMP signaling is precisely regulated and perturbation of BMP signaling is connected to multiple diseases, including musculoskeletal diseases. In this review, we will summarize the recent progress in elucidation of BMP signal transduction, how overactive BMP signaling is involved in the pathogenesis of heterotopic ossification and Duchenne muscular dystrophy, and discuss possible therapeutic strategies for treatment of these diseases. 相似文献
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Pau B. Esparza-Moltó Cristina Nuevo-Tapioles José M. Cuezva 《Cellular and molecular life sciences : CMLS》2017,74(12):2151-2166
The mitochondrial H+-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H+-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H+-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H+-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H+-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases. 相似文献
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In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau
protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide
(NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade
HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species.
A prerequisite for O
2
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in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone
was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation.
Using uric acid to interfere with signal transmission elicited by NO/O
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blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O
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coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome.
Received 14 August 2007; received after revision 4 October 2007; accepted 22 October 2007 相似文献
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Terhi Vihervaara Riikka-Liisa Uronen Gerd Wohlfahrt Ingemar Björkhem Elina Ikonen Vesa M. Olkkonen 《Cellular and molecular life sciences : CMLS》2011,68(3):537-551
ORP1L is an oxysterol binding homologue that regulates late endosome (LE) positioning. We show that ORP1L binds several oxysterols
and cholesterol, and characterize a mutant, ORP1L Δ560–563, defective in oxysterol binding. While wild-type ORP1L clusters
LE, ORP1L Δ560–563 induces LE scattering, which is reversed by disruption of the endoplasmic reticulum (ER) targeting FFAT
motif, suggesting that it is due to enhanced LE–ER interactions. Endosome motility is reduced upon overexpression of ORP1L.
Both wild-type ORP1L and the Δ560–563 mutant induce the recruitment of both dynactin and kinesin-2 on LE. Most of the LE decorated
by overexpressed ORP1L fail to accept endocytosed dextran or EGF, and the transfected cells display defective degradation
of internalized EGF. ORP1L silencing in macrophage foam cells enhances endosome motility and results in inhibition of [3H]cholesterol efflux to apolipoprotein A-I. These data demonstrate that LE motility and functions in both protein and lipid
transport are regulated by ORP1L. 相似文献