Abstract TP264: Actin Reorganization is a Rapid and Reversible Adaptive Response by Neurons Exposed to Ischemic and Excitotoxic Injury
            in vitro
            and
            in vivo

Postmenopausal osteoporosis represents a failure of the response by which bone cells adapt bone mass and architecture to be sufficiently strong to withstand loading without fracture. To address why this failure should be associated with oestrogen withdrawal, we investigated the ulna's adaptive response to mechanical loading in adult female mice lacking oestrogen receptor-alpha (ERalpha(-/-)), those lacking oestrogen receptor-beta (ERbeta(-/-)) and their wild-type littermates. In wild-type mice, short periods of physiologic cyclic compressive loading of the ulna in vivo over a 2-week period stimulates new bone formation. In ERalpha(-/-) and ERbeta(-/-) mice this osteogenic response was respectively threefold and twofold less (P<0.05). In vitro, primary cultures of osteoblast-like cells derived from these mice were subjected to a single short period of mechanical strain. Twenty-four hours after strain the number of wild-type cells was 61+/-25% higher than in unstrained controls (P<0.05), whereas in ERalpha(-/-) cells there was no strain-related increase in cell number. However, the strain-related response of ERalpha(-/-) cells could be partially rescued by transfection with functional human ERalpha (P<0.05). ERbeta(-/-) cells showed a 125+/-40% increase in cell number following strain. This was significantly greater than in wild types (P<0.05).These data support previous findings that functional ERalpha is required for the full osteogenic response to mechanical loading and particularly the stage of this response, which involves an increase in osteoblast number. ERbeta appears to depress the ERalpha-mediated strain-related increase in osteoblast number in vitro, but in female transgenic mice in vivo the constitutive absence of either ERalpha or ERbeta appears to diminish the osteogenic response to loading.

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NaCI acts as a direct modulator in the salt adaptive response: Salt-dependent activation of glucosylglycerol synthesis in vivo and in vitro

Journal of Plant Physiology ◽

10.1016/s0176-1617(96)80101-5 ◽

1996 ◽

Vol 149 (6) ◽

pp. 746-752 ◽

Cited By ~ 17

Author(s):

Martin Hagemann ◽

Arne Schoor ◽

Norbert Erdmann

Keyword(s):

Adaptive Response

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Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00168.2011 ◽

2012 ◽

Vol 302 (4) ◽

pp. H983-H991 ◽

Cited By ~ 31

Author(s):

Ji Zhang ◽

Morton H. Friedman

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Adaptive Response ◽

Vascular Endothelial Cells ◽

Endothelial Permeability ◽

Global Gene Expression ◽

Vascular Endothelial ◽

Acute Increase

The adaptation of vascular endothelial cells to shear stress alteration induced by global hemodynamic changes, such as those accompanying exercise or digestion, is an essential component of normal endothelial physiology in vivo. An understanding of the transient regulation of endothelial phenotype during adaptation to changes in mural shear will advance our understanding of endothelial biology and may yield new insights into the mechanism of atherogenesis. In this study, we characterized the adaptive response of arterial endothelial cells to an acute increase in shear stress magnitude in well-defined in vitro settings. Porcine endothelial cells were preconditioned by a basal level shear stress of 15 ± 15 dyn/cm2 at 1 Hz for 24 h, after which an acute increase in shear stress to 30 ± 15 dyn/cm2 was applied. Endothelial permeability nearly doubled after 40-min exposure to the elevated shear stress and then decreased gradually. Transcriptomics studies using microarray techniques identified 86 genes that were sensitive to the elevated shear. The acute increase in shear stress promoted the expression of a group of anti-inflammatory and antioxidative genes. The adaptive response of the global gene expression profile is triphasic, consisting of an induction period, an early adaptive response (ca. 45 min) and a late remodeling response. Our results suggest that endothelial cells exhibit a specific phenotype during the adaptive response to changes in shear stress; this phenotype is different than that of fully adapted endothelial cells.

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Extracellular purines' action on glomerular albumin permeability in isolated rat glomeruli: insights into the pathogenesis of albuminuria

AJP Renal Physiology ◽

10.1152/ajprenal.00567.2015 ◽

2016 ◽

Vol 311 (1) ◽

pp. F103-F111 ◽

Cited By ~ 11

Author(s):

Małgorzata Kasztan ◽

Agnieszka Piwkowska ◽

Ewelina Kreft ◽

Dorota Rogacka ◽

Irena Audzeyenka ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Guanylate Cyclase ◽

Receptor Activation ◽

Actin Reorganization ◽

Atp Analogs ◽

Oxide Synthase ◽

Isolated Rat

Purinoceptors (adrengeric receptors and P2 receptors) are expressed on the cellular components of the glomerular filtration barrier, and their activation may affect glomerular permeability to albumin, which may ultimately lead to albuminuria, a well-established risk factor for the progression of chronic kidney disease and development of cardiovascular diseases. We investigated the mechanisms underlying the in vitro and in vivo purinergic actions on glomerular filter permeability to albumin by measuring convectional albumin permeability ( Palb) in a single isolated rat glomerulus based on the video microscopy method. Primary cultured rat podocytes were used for the analysis of Palb, cGMP accumulation, PKG-Iα dimerization, and immunofluorescence. In vitro, natural nucleotides (ATP, ADP, UTP, and UDP) and nonmetabolized ATP analogs (2-meSATP and ATP-γ-S) increased Palb in a time- and concentration-dependent manner. The effects were dependent on P2 receptor activation, nitric oxide synthase, and cytoplasmic guanylate cyclase. ATP analogs significantly increased Palb, cGMP accumulation, and subcortical actin reorganization in a PKG-dependent but nondimer-mediated route in cultured podocytes. In vivo, 2-meSATP and ATP-γ-S increased Palb but did not significantly affect urinary albumin excretion. Both agonists enhanced the clathrin-mediated endocytosis of albumin in podocytes. A product of adenine nucleotides hydrolysis, adenosine, increased the permeability of the glomerular barrier via adrenergic receptors in a dependent and independent manner. Our results suggest that the extracellular nucleotides that stimulate an increase of glomerular Palb involve nitric oxide synthase and cytoplasmic guanylate cyclase with actin reorganization in podocytes.

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Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

10.1101/711895 ◽

2019 ◽

Author(s):

Gonghong Yan ◽

Heping Wang ◽

Augustin Luna ◽

Behnaz Bozorgui ◽

Xubin Li ◽

...

Keyword(s):

Breast Cancer ◽

Lipid Metabolism ◽

Adaptive Response ◽

Structural Changes ◽

Breast Cancers ◽

Kinase Activation ◽

Metabolism Enzymes ◽

Chromosomal Amplifications

AbstractThe development of effective targeted therapies for the treatment of basal-like breast cancers remains challenging. Here, we demonstrate that BET inhibition induces a multi-faceted adaptive response program leading to MCL1 protein-driven evasion of apoptosis in breast cancers. Consequently, co-targeting MCL1 and BET is highly synergistic in in vitro and in vivo breast cancer models. Drug response and genomics analyses revealed that MCL1 copy number alterations, including low-level gains, are selectively enriched in basal-like breast cancers and associated with effective BET and MCL1 co-targeting. The mechanism of adaptive response to BET inhibition involves upregulation of critical lipid metabolism enzymes including the rate-limiting enzyme stearoyl-CoA desaturase (SCD). Changes in the lipid metabolism are associated with increases in cell motility and membrane fluidity as well as transitions in cell morphology and adhesion. The structural changes in the cell membrane leads to re-localization and activation of HER2/EGFR which can be interdicted by inhibiting SCD activity. Active HER2/EGFR, in turn, induces accumulation of MCL1 protein and therapeutic vulnerability to MCL1 inhibitors. The BET protein, lipid metabolism and receptor tyrosine kinase activation cascade is observed in patient cohorts of basal-like and HER2-amplified breast cancers. The high frequency of MCL1 chromosomal amplifications (>30%) and gains (>50%) in basal-like breast cancers suggests that BET and MCL1 co-inhibition may have therapeutic utility in this aggressive subtype.

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Cortactin Promotes Migration and Platelet-derived Growth Factor-induced Actin Reorganization by Signaling to Rho-GTPases

Molecular Biology of the Cell ◽

10.1091/mbc.e08-12-1180 ◽

2009 ◽

Vol 20 (14) ◽

pp. 3209-3223 ◽

Cited By ~ 75

Author(s):

Frank P.L. Lai ◽

Malgorzata Szczodrak ◽

J. Margit Oelkers ◽

Markus Ladwein ◽

Filippo Acconcia ◽

...

Keyword(s):

Cell Migration ◽

Growth Factor ◽

Rho Gtpases ◽

Platelet Derived Growth Factor ◽

Actin Assembly ◽

Actin Reorganization ◽

Directed Cell Migration ◽

Syndrome Protein

Dynamic actin rearrangements are initiated and maintained by actin filament nucleators, including the Arp2/3-complex. This protein assembly is activated in vitro by distinct nucleation-promoting factors such as Wiskott-Aldrich syndrome protein/Scar family proteins or cortactin, but the relative in vivo functions of each of them remain controversial. Here, we report the conditional genetic disruption of murine cortactin, implicated previously in dynamic actin reorganizations driving lamellipodium protrusion and endocytosis. Unexpectedly, cortactin-deficient cells showed little changes in overall cell morphology and growth. Ultrastructural analyses and live-cell imaging studies revealed unimpaired lamellipodial architecture, Rac-induced protrusion, and actin network turnover, although actin assembly rates in the lamellipodium were modestly increased. In contrast, platelet-derived growth factor-induced actin reorganization and Rac activation were impaired in cortactin null cells. In addition, cortactin deficiency caused reduction of Cdc42 activity and defects in random and directed cell migration. Reduced migration of cortactin null cells could be restored, at least in part, by active Rac and Cdc42 variants. Finally, cortactin removal did not affect the efficiency of receptor-mediated endocytosis. Together, we conclude that cortactin is fully dispensable for Arp2/3-complex activation during lamellipodia protrusion or clathrin pit endocytosis. Furthermore, we propose that cortactin promotes cell migration indirectly, through contributing to activation of selected Rho-GTPases.

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Global Gene Expression in Staphylococcus aureus Biofilms

Journal of Bacteriology ◽

10.1128/jb.186.14.4665-4684.2004 ◽

2004 ◽

Vol 186 (14) ◽

pp. 4665-4684 ◽

Cited By ~ 385

Author(s):

Karen E. Beenken ◽

Paul M. Dunman ◽

Fionnuala McAleese ◽

Daphne Macapagal ◽

Ellen Murphy ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Adaptive Response ◽

Biofilm Formation ◽

Global Gene Expression ◽

Growth Conditions ◽

Anaerobic Growth ◽

Over Expression ◽

Custom Made

ABSTRACT We previously demonstrated that mutation of the staphylococcal accessory regulator (sarA) in a clinical isolate of Staphylococcus aureus (UAMS-1) results in an impaired capacity to form a biofilm in vitro (K. E. Beenken, J. S. Blevins, and M. S. Smeltzer, Infect. Immun. 71:4206-4211, 2003). In this report, we used a murine model of catheter-based biofilm formation to demonstrate that a UAMS-1 sarA mutant also has a reduced capacity to form a biofilm in vivo. Surprisingly, mutation of the UAMS-1 ica locus had little impact on biofilm formation in vitro or in vivo. In an effort to identify additional loci that might be relevant to biofilm formation and/or the adaptive response required for persistence of S. aureus within a biofilm, we isolated total cellular RNA from UAMS-1 harvested from a biofilm grown in a flow cell and compared the transcriptional profile of this RNA to RNA isolated from both exponential- and stationary-phase planktonic cultures. Comparisons were done using a custom-made Affymetrix GeneChip representing the genomic complement of six strains of S. aureus (COL, N315, Mu50, NCTC 8325, EMRSA-16 [strain 252], and MSSA-476). The results confirm that the sessile lifestyle associated with persistence within a biofilm is distinct by comparison to the lifestyles of both the exponential and postexponential phases of planktonic culture. Indeed, we identified 48 genes in which expression was induced at least twofold in biofilms over expression under both planktonic conditions. Similarly, we identified 84 genes in which expression was repressed by a factor of at least 2 compared to expression under both planktonic conditions. A primary theme that emerged from the analysis of these genes is that persistence within a biofilm requires an adaptive response that limits the deleterious effects of the reduced pH associated with anaerobic growth conditions.

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Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies

Journal of Toxicology ◽

10.1155/2012/308594 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Linda R. Barone ◽

Scott Boyer ◽

James R. Damewood ◽

James Fikes ◽

Paul J. Ciaccio

Keyword(s):

Adaptive Response ◽

Reproductive Organs ◽

Liver Necrosis ◽

Neutral Compounds ◽

Preclinical Species ◽

Kidney Liver ◽

Histologic Changes ◽

Lung Lymph

While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZenecain vivotoxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validatedin silicoandin vitromodels. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics.

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The C-terminal domain of EFA6A interacts directly with F-actin and assembles F-actin bundles

Scientific Reports ◽

10.1038/s41598-019-55630-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Eric Macia ◽

Mariagrazia Partisani ◽

Hong Wang ◽

Sandra Lacas-Gervais ◽

Christophe Le Clainche ◽

...

Keyword(s):

Actin Polymerization ◽

Neuronal Morphogenesis ◽

Actin Reorganization ◽

Actin Bundles ◽

Actin Organization ◽

C Terminus ◽

Membrane Protrusions ◽

Actin Cables

AbstractThe Arf6-specific exchange factor EFA6 is involved in the endocytic/recycling pathway for different cargos. In addition EFA6 acts as a powerful actin cytoskeleton organizer, a function required for its role in the establishment of the epithelial cell polarity and in neuronal morphogenesis. We previously showed that the C-terminus of EFA6 (EFA6-Ct) is the main domain which contributes to actin reorganization. Here, by in vitro and in vivo experiments, we sought to decipher, at the molecular level, how EFA6 controls the dynamic and structuring of actin filaments. We showed that EFA6-Ct interferes with actin polymerization by interacting with and capping actin filament barbed ends. Further, in the presence of actin mono-filaments, the addition of EFA6-Ct triggered the formation of actin bundles. In cells, when the EFA6-Ct was directed to the plasma membrane, as is the case for the full-length protein, its expression induced the formation of membrane protrusions enriched in actin cables. Collectively our data explain, at least in part, how EFA6 plays an essential role in actin organization by interacting with and bundling F-actin.

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