Abstract:
:The endoplasmic reticulum (ER) has emerged as a critical regulator of cell survival. IRE1 is a transmembrane protein with kinase and RNase activities that is localized to the ER and that promotes resistance to ER stress. We showed a mechanism by which IRE1 conferred protection against ER stress-mediated cell death. IRE1 signaling prevented ER membrane permeabilization mediated by Bax and Bak and cell death in cells experiencing ER stress. Suppression of IRE1 signaling triggered by its kinase activity led to the accumulation of the BH3 domain-containing protein Bnip3, which in turn triggered the oligomerization of Bax and Bak in the ER membrane and ER membrane permeabilization. Consequently, in response to ER stress, cells deficient in IRE1 were susceptible to leakage of ER contents, which was associated with the accumulation of calcium in mitochondria, oxidative stress in the cytosol, and ultimately cell death. Our results reveal a role for IRE1 in preventing a cell death-initializing step that emanates from the ER and provide a potential target for treating diseases characterized by ER stress, including diabetes and Wolfram syndrome.
journal_name
Sci Signaljournal_title
Science signalingauthors
Kanekura K,Ma X,Murphy JT,Zhu LJ,Diwan A,Urano Fdoi
10.1126/scisignal.aaa0341subject
Has Abstractpub_date
2015-06-23 00:00:00pages
ra62issue
382eissn
1945-0877issn
1937-9145pii
8/382/ra62journal_volume
8pub_type
杂志文章abstract::The cytoplasmic phosphatase PTPN22 (protein tyrosine phosphatase nonreceptor type 22) plays a key role in regulating lymphocyte homeostasis, which ensures that the total number of lymphocytes in the periphery remains relatively constant. Mutations in PTPN22 confer an increased risk of developing autoimmune diseases; h...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003365
更新日期:2012-11-27 00:00:00
abstract::Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-β (Aβ) in the walls of cerebral vessels. CAA and Aβ deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascul...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aaf6240
更新日期:2016-05-24 00:00:00
abstract::The K+/Cl- cotransporter KCC2 is a molecular switch between excitatory and inhibitory effects of GABAergic inputs into neurons. In a pair of exciting studies, Watanabe et al. and Pisella et al. elucidate the role of KCC2 dephosphorylation in this process and reveal its consequences for neurodevelopment and nervous sys...
journal_title:Science signaling
pub_type: 评论,杂志文章,评审
doi:10.1126/scisignal.aay8960
更新日期:2019-10-15 00:00:00
abstract::Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2001556
更新日期:2011-03-29 00:00:00
abstract::Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brai...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aay9452
更新日期:2020-01-21 00:00:00
abstract::Insulin secretion from pancreatic β cells is controlled by nutrients, hormones, and neurotransmitters. Unlike the latter, which work through classic receptors, glucose and most other nutrients do not interact with membrane receptors but must be metabolized by β cells to induce insulin secretion. Studies have revealed ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003325
更新日期:2012-08-28 00:00:00
abstract::MicroRNAs (miRNAs), key posttranscriptional regulators of many biological processes, have been implicated in many diseases, including cancer. In a recent paper, Avraham and colleagues take a systems biology approach to determine whether and how miRNAs are involved in the regulation of oncogenic signaling networks down...
journal_title:Science signaling
pub_type: 评论,杂志文章,评审
doi:10.1126/scisignal.2002182
更新日期:2011-07-26 00:00:00
abstract::Vitamin D receptor represses basal autophagy in breast tissue, which is derepressed by vitamin D, slowing cancer progression. ...
journal_title:Science signaling
pub_type: 评论,杂志文章
doi:10.1126/scisignal.aan2526
更新日期:2017-03-21 00:00:00
abstract::Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, we ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aat5916
更新日期:2018-10-23 00:00:00
abstract::Signaling pathways control cell fate decisions that ultimately determine the behavior of cancer cells. Therefore, the dynamics of pathway activity may contain prognostically relevant information different from that contained in the static nature of other types of biomarkers. To investigate this hypothesis, we characte...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aab0990
更新日期:2015-12-22 00:00:00
abstract::Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in re...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.3145re8
更新日期:2010-10-26 00:00:00
abstract::Huntington's disease (HD) is a neurodegenerative disease caused by an expansion in the huntingtin protein (also called Htt) that induces neuronal cell death with age. We found that the treatment of 12-month-old symptomatic heterozygous and homozygous zQ175 huntingtin knockin mice for 12 weeks with CTEP, a negative all...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aan6387
更新日期:2017-12-19 00:00:00
abstract::Signaling by the transforming growth factor-β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ce...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aam7464
更新日期:2017-10-24 00:00:00
abstract::The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.abd2494
更新日期:2020-12-15 00:00:00
abstract::The interplay between calcium ion (Ca(2+)) and cyclic adenosine monophosphate (cAMP) signaling underlies crucial aspects of cell homeostasis. The membrane-bound Ca(2+)-regulated adenylyl cyclases (ACs) are pivotal points of this integration. These enzymes display high selectivity for Ca(2+) entry arising from the acti...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2002299
更新日期:2012-04-10 00:00:00
abstract::One reported function of the tumor suppressor p19(Arf) is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19(Arf), p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19(Arf)...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2000053
更新日期:2009-08-18 00:00:00
abstract::Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.aaf7067
更新日期:2016-04-26 00:00:00
abstract::Ewing's sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aam8429
更新日期:2017-10-03 00:00:00
abstract::The TRAF [tumor necrosis factor receptor-associated factor] family of cytoplasmic adaptor proteins link cell-surface receptors to intracellular signaling pathways that regulate innate and adaptive immune responses. In response to activation of RIG-I (retinoic acid-inducible gene I), a component of a pattern recognitio...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003152
更新日期:2012-11-13 00:00:00
abstract::Double knockout of PTEN and LKB1-genes encoding phosphatase and tensin homolog and liver kinase B1, respectively-leads to the spontaneous development of cancer in mice. PTEN converts phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2), whereas LKB1 activates the 5' adeno...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.aac8321
更新日期:2015-09-01 00:00:00
abstract::Jiang et al. (Research Article, 11 October 2011, DOI: 10.1126/scisignal.2002152) used a combined experimental and computational modeling approach to study the dynamic response behavior of covalent modification cycles in the presence of downstream targets ("loads"). Despite remarkable agreement between experiments and ...
journal_title:Science signaling
pub_type: 评论,信件
doi:10.1126/scisignal.2002699
更新日期:2012-01-03 00:00:00
abstract::Skeletal muscle mass is regulated by activity, metabolism, and the availability of nutrients. During muscle atrophy, MNK2 expression increases. We found that MNK2 (mitogen-activated protein kinase-interacting kinase 2), but not MNK1, inhibited proteins involved in promoting protein synthesis, including eukaryotic tran...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2002466
更新日期:2012-02-14 00:00:00
abstract::The hexosamine biosynthetic pathway, whose end product is UDP-N acetylglucosamine (UDP-GlcNAc), lies at the base of cellular glycosylation pathways, including glycosylation of lipids, formation of heparin sulfated proteoglycans, and N- and O-linked glycosylation of proteins. Forward genetic studies in Drosophila have ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2002789
更新日期:2012-01-17 00:00:00
abstract::The mechanisms that determine localized formation of reactive oxygen species (ROS) through NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) family members in nonphagocytic cells are unknown. We show that the c-Src substrate proteins Tks4 (tyrosine kinase substrate with four SH3 domains...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2000370
更新日期:2009-09-15 00:00:00
abstract::This week, Science Signaling highlights research that uses computational and cell biology approaches to uncover the molecular mechanisms underlying diseases of the central nervous system. In particular, research featured explores the neuronal response to stress due to excess excitatory stimuli, multiple roles for pres...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.2004456
更新日期:2013-07-09 00:00:00
abstract::This two-part lecture introduces students to the scientific computing language MATLAB. Prior computer programming experience is not required. The lectures present basic concepts of computer programming logic that tend to cause difficulties for beginners in addition to concepts that relate specifically to the MATLAB la...
journal_title:Science signaling
pub_type:
doi:10.1126/scisignal.2001984
更新日期:2011-09-13 00:00:00
abstract::Store-operated Ca2+ entry (SOCE) channels are highly selective Ca2+ channels activated by the endoplasmic reticulum (ER) sensors STIM1 and STIM2. Their direct interaction with the pore-forming plasma membrane ORAI proteins (ORAI1, ORAI2, and ORAI3) leads to sustained Ca2+ fluxes that are critical for many cellular fun...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aav4663
更新日期:2019-04-23 00:00:00
abstract::Mechanical loading of the skeleton is essential for the development, growth, and maintenance of strong, weight-bearing bones. Bone strength is plastic and can be modulated in adults, as illustrated by the increased bone mass in the playing arms of athletes as compared with their nonplaying arms. Our studies have shown...
journal_title:Science signaling
pub_type:
doi:10.1126/scisignal.268pt3
更新日期:2009-04-28 00:00:00
abstract::Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aaw5573
更新日期:2019-10-22 00:00:00
abstract::Cross-linking of proteins by mammalian transglutaminases (TGs) plays important roles in physiological phenomena such as blood coagulation and skin formation. We show that Drosophila TG suppressed innate immune signaling in the gut. RNA interference (RNAi) directed against TG reduced the life span of flies reared under...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003970
更新日期:2013-07-23 00:00:00