Abstract：
:Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Sannino S,Guerriero CJ,Sabnis AJ,Stolz DB,Wallace CT,Wipf P,Watkins SC,Bivona TG,Brodsky JLdoi
10.1242/jcs.217760subject
Has Abstractpub_date
2018-09-05 00:00:00issue
17eissn
0021-9533issn
1477-9137pii
jcs.217760journal_volume
131pub_type
杂志文章abstract：:Cyclic stretch is an artificial model of mechanical force loading, which induces the reorientation of vascular endothelial cells and their stress fibers in a direction perpendicular to the stretch axis. Rho family GTPases are crucial for cyclic-stretch-induced endothelial cell reorientation; however, the mechanism und...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.157503
更新日期：2015-05-01 00:00:00
abstract：:Mammalian melanocytes can produce two basic types of melanin, eumelanin and pheomelanin, within discrete organelles termed melanosomes. The physiological signals that regulate this switch are extrinsic to the melanocyte, and include alpha-melanocyte stimulating hormone and the agouti protein. Tyrosinase, encoded at th...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1995-06-01 00:00:00
abstract：:Polarity of many cell types is controlled by a protein complex consisting of Bazooka/PAR-3 (Baz), PAR-6 and atypical protein kinase C (aPKC). In Drosophila, the Baz-PAR-6-aPKC complex is required for the control of cell polarity in the follicular epithelium, in ectodermal epithelia and neuroblasts. aPKC is the main si...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.052514
更新日期：2009-10-15 00:00:00
abstract：:In the fission yeast Schizosaccharomyces pombe, the protein kinase Chk1 has an essential role in transducing a delay signal to the cell cycle machinery in the presence of DNA damage. Fission yeast cells lacking the chk1 gene do not delay progression of the cell cycle in response to damage and are thus sensitive to DNA...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.00133
更新日期：2002-12-01 00:00:00
abstract：:Epithelial junctions depend on intercellular interactions between β(1) subunits of the Na(+)/K(+)-ATPase molecules of neighboring cells. The interaction between dog and rat subunits is less effective than the interaction between two dog β(1) subunits, indicating the importance of species-specific regions for β(1)-β(1)...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.100149
更新日期：2012-03-15 00:00:00
abstract：:Previous work has shown that phorbol esters or diacylglycerol trigger cortical granule exocytosis in Xenopus oocytes. We sought to identify the isoform(s) of protein kinase C (PKC) that mediate(s) this regulated secretory event. Because this process is initiated by lipid activators of PKC but is independent of calcium...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2002-03-15 00:00:00
abstract：:Gene expression of malaria parasites is mediated by the apicomplexan Apetala2 (ApiAP2) transcription factor family. Different ApiAP2s control gene expression at distinct stages in the complex life cycle of the parasite, ensuring timely expression of stage-specific genes. ApiAP2s recognize short cis-regulatory elements...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.210971
更新日期：2018-10-22 00:00:00
abstract：:Cadherin has an intimate spatial relationship with actin filaments (AF) in various types of cells, forming the cell-to-cell adherens junction (AJ). We compared the AJ/AF relationship between non-polarized fibroblasts (NRK cells) and polarized epithelial cells (MTD-1A cells). E/P-cadherin, alpha-catenin, ZO-1 and vincu...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1995-01-01 00:00:00
abstract：:The study of plasma membrane and phagosome membrane of Dictyostelium discoideum was performed using 2 lectins: concanavalin A (Con A) and Wheat Germ Agglutinin (WGA), and 2 markers of anionic sites: colloidal iron hydroxide (CIH) and cationized ferritin (CF). These labellings were applied to fixed partially broken cel...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1980-02-01 00:00:00
abstract：:Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins. Here we demonstrate relocalization and novel interactions of Mdm2 with the promyelocytic leukemia (PML) protein following cellular stress and DNA damage. We show that Mdm2 and PML interact ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.00714
更新日期：2003-10-01 00:00:00
abstract：:During the interphase to metaphase transition, microtubules are destabilized by a cdc2 kinase-dependent phosphorylation event. This destabilization is due to a dramatic increase in the rate at which each growing microtubule starts to shrink (catastrophe rate). In principle, this could be brought about by lowering the ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1992-01-01 00:00:00
abstract：:We report the first direct analysis of the endogenous β-catenin phosphorylation activity in colon cancer SW480 cells. By comparing parental SW480 cells that harbor a typical truncated adenomatous polyposis coli (APC) form, cells expressing full-length APC and APC-depleted cells, we provide the formal demonstration tha...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.131045
更新日期：2014-04-15 00:00:00
abstract：:Fatty acids constitute an important energy source for various tissues. The mechanisms that mediate and control uptake of free fatty acids from the circulation, however, are poorly understood. Here we show that efficient fatty-acid uptake by yeast cells requires the protein kinase Ypk1, the orthologue of the human seru...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.063073
更新日期：2010-07-01 00:00:00
abstract：:Endocytosis and recycling of membrane proteins are key processes for nutrient uptake, receptor signaling and synaptic transmission. Different steps in these fission and fusion cycles have been proposed to be regulated by physiological changes in plasma membrane (PM) phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.020792
更新日期：2008-05-01 00:00:00
abstract：:Immunofluorescent anti-tubulin staining has been used to follow nuclear progression from dictyate to metaphase II during meiotic maturation of mouse oocytes in vitro. Antibody directed against tubulin isolated from sea-urchin eggs decorates the metaphase I and metaphase II spindles, as well as the cytoplasmic bridge, ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1978-02-01 00:00:00
abstract：:Recently, several 3D images of kinesin-family motor domains interacting with microtubules have been obtained by analysis of electron microscope images of frozen hydrated complexes at much higher resolutions (9-12 A) than in previous reports (15-30 A). The high-resolution maps show a complex interaction interface betwe...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.016931
更新日期：2007-11-15 00:00:00
abstract：:The alpha6beta4 integrin is located at the basal surface of keratinocytes, in hemidesmosomal structures that mediate stable adhesion of epidermal cells to the underlying basement membrane component laminin-5. The absence of alpha6beta4 integrin causes junctional epidermolysis bullosa, a severe blistering disease of th...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.01689
更新日期：2005-03-01 00:00:00
abstract：:Intermediate filament (IF) dynamics during organelle transport and their role in organelle movement were studied using Xenopus laevis melanophores. In these cells, pigment granules (melanosomes) move along microtubules and microfilaments, toward and away from the cell periphery in response to alpha-melanocyte stimulat...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.046789
更新日期：2009-08-15 00:00:00
abstract：:The growth of two human diploid skin fibroblast cell lines, originally grown in medium supplemented with foetal bovine serum and later adapted to medium supplemented with newborn bovine, bovine calf or horse serum, has been studied. Prolonged generation times increased cell volumes and decreased plating efficiencies w...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
abstract：:The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.187260
更新日期：2016-08-15 00:00:00
abstract：:Delayed wound healing caused by inefficient re-epithelialization underlines chronic skin lesions such as those found in diabetes. The dioxin receptor (AhR) modulates cell plasticity and migration and its activation by occupational polycyclic aromatic hydrocarbons (PAHs) results in severe skin lesions such as contact h...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.047274
更新日期：2009-06-01 00:00:00
abstract：:Two variants (74AD and 74FL) established from rat ascites hepatoma AH7974 were examined for the production of glycosaminoglycans in culture. There was no difference between the adhesive (74AD) and the floating (74FL) variants in quantity of glycosaminoglycans produced by their cultivation in minimum essential medium s...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1988-08-01 00:00:00
abstract：:Misfolded endoplasmic reticulum (ER) proteins are dislocated towards the cytosol and degraded by the ubiquitin-proteasome system in a process called ER-associated protein degradation (ERAD). During infection with human cytomegalovirus (HCMV), the viral US2 protein targets HLA class I molecules (HLA-I) for degradation ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.206839
更新日期：2017-09-01 00:00:00
abstract：:Toxoplasma gondii is an obligate intracellular parasite that infects a wide variety of vertebrate cells including macrophages. We have used a combination of video microscopy and fluorescence localization to examine the entry of Toxoplasma into macrophages and nonphagocytic host cells. Toxoplasma actively invaded host ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1995-06-01 00:00:00
abstract：:In plant cells nucleolar fibrillar centres (FCs) undergo ultrastructural changes, depending on the nucleolar activity. We have found two types of FC structure in nucleoli with either high or low activity, to which we have given the conventional names of homogeneous and heterogeneous, respectively. The first type is ch...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1982-12-01 00:00:00
abstract：:Besides regulating glucose levels, insulin has been reported to participate actively in many other functions, including modulating inflammatory reactions. In this study we investigated how topical insulin application would affect the diabetic wound healing process. We found that the excessive expression of insulin-deg...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.235838
更新日期：2020-10-12 00:00:00
abstract：:We have isolated suppressors of the deletion allele of delta-tubulin, uni3-1, in the biflagellate green alga Chlamydomonas reinhardtii. The deletion of delta-tubulin produces cells that assemble zero, one or two flagella and have basal bodies composed primarily of doublet rather than triplet microtubules. Flagellar nu...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.00859
更新日期：2004-01-15 00:00:00
abstract：:During their development, mammalian oocytes acquire the ability to resume meiosis. We demonstrate that the concentration of p34cdc2 increases during the acquisition of meiotic competence, as determined by immunoblotting, whereas the concentration of cyclin B1 decreases. Laser-scanning confocal microscopy corroborated ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1996-09-01 00:00:00
abstract：:We have identified a novel mammalian protein, MIR1, with microtubule-binding activity. MIR1 is a relative of MID1/midin, the protein implicated in Opitz G/BBB syndrome. In tissue culture cells, MIR1 is enriched at the centrosome. MIR1 dissociates from centrosomes at the G2/M transition and is recruited back to spindle...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2002-09-01 00:00:00
abstract：:Although telomere formation occurs through a different mechanism in Drosophila compared with other organisms, telomere associations result from mutations in homologous genes, indicating the involvement of similar pathways in chromosome end protection. We report here that mutations of the Drosophila melanogaster gene C...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.035097
更新日期：2009-03-15 00:00:00
