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81.
Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
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Chris D Madsen Jesper T Pedersen Freja A Venning Lukram Babloo Singh Emad Moeendarbary Guillaume Charras Thomas R Cox Erik Sahai Janine T Erler 《EMBO reports》2015,16(10):1394-1408
Cancer‐associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF‐mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia‐inducible factor (HIF)‐1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF‐1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co‐injected with tumour cells similarly prevents CAF‐induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications. 相似文献
82.
Computational modeling of the N‐terminus of the human dopamine transporter and its interaction with PIP2‐containing membranes
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George Khelashvili Milka Doktorova Michelle A. Sahai Niklaus Johner Lei Shi Harel Weinstein 《Proteins》2015,83(5):952-969
The dopamine transporter (DAT) is a transmembrane protein belonging to the family of neurotransmitter:sodium symporters (NSS). Members of the NSS are responsible for the clearance of neurotransmitters from the synaptic cleft, and for their translocation back into the presynaptic nerve terminal. The DAT contains long intracellular N‐ and C‐terminal domains that are strongly implicated in the transporter function. The N‐terminus (N‐term), in particular, regulates the reverse transport (efflux) of the substrate through DAT. Currently, the molecular mechanisms of the efflux remain elusive in large part due to lack of structural information on the N‐terminal segment. Here we report a computational model of the N‐term of the human DAT (hDAT), obtained through an ab initio structure prediction, in combination with extensive atomistic molecular dynamics (MD) simulations in the context of a lipid membrane. Our analysis reveals that whereas the N‐term is a highly dynamic domain, it contains secondary structure elements that remain stable in the long MD trajectories of interactions with the bilayer (totaling >2.2 μs). Combining MD simulations with continuum mean‐field modeling we found that the N‐term engages with lipid membranes through electrostatic interactions with the charged lipids PIP2 (phosphatidylinositol 4,5‐Biphosphate) or PS (phosphatidylserine) that are present in these bilayers. We identify specific motifs along the N‐term implicated in such interactions and show that differential modes of N‐term/membrane association result in differential positioning of the structured segments on the membrane surface. These results will inform future structure‐based studies that will elucidate the mechanistic role of the N‐term in DAT function. Proteins 2015; 83:952–969. © 2015 Wiley Periodicals, Inc. 相似文献
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Keval Bollavaram Tiffanie H. Leeman Maggie W. Lee Akhil Kulkarni Sophia G. Upshaw Jiabei Yang Hannah Song Manu O. Platt 《Protein science : a publication of the Protein Society》2021,30(6):1131
SARS‐CoV‐2 is the coronavirus responsible for the COVID‐19 pandemic. Proteases are central to the infection process of SARS‐CoV‐2. Cleavage of the spike protein on the virus''s capsid causes the conformational change that leads to membrane fusion and viral entry into the target cell. Since inhibition of one protease, even the dominant protease like TMPRSS2, may not be sufficient to block SARS‐CoV‐2 entry into cells, other proteases that may play an activating role and hydrolyze the spike protein must be identified. We identified amino acid sequences in all regions of spike protein, including the S1/S2 region critical for activation and viral entry, that are susceptible to cleavage by furin and cathepsins B, K, L, S, and V using PACMANS, a computational platform that identifies and ranks preferred sites of proteolytic cleavage on substrates, and verified with molecular docking analysis and immunoblotting to determine if binding of these proteases can occur on the spike protein that were identified as possible cleavage sites. Together, this study highlights cathepsins B, K, L, S, and V for consideration in SARS‐CoV‐2 infection and presents methodologies by which other proteases can be screened to determine a role in viral entry. This highlights additional proteases to be considered in COVID‐19 studies, particularly regarding exacerbated damage in inflammatory preconditions where these proteases are generally upregulated. 相似文献
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Amin Arqam Awais Muhammad Sahai Shalini Hussain Waqar Rasool Nouman 《International journal of peptide research and therapeutics》2021,27(2):1315-1329
International Journal of Peptide Research and Therapeutics - DNA replication is one of the specific processes to be considered in all the living organisms, specifically eukaryotes. The prevalence... 相似文献
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Sarma MV Kumar V Saharan K Srivastava R Sharma AK Prakash A Sahai V Bisaria VS 《Journal of applied microbiology》2011,111(2):456-466
Aims: Fluorescent pseudomonads are widely used as bioinoculants for improving plant growth and controlling phytopathogenic fungi. Piriformospora indica (Pi), a symbiotic root endophyte, also has beneficial effects on a number of plants. The present study focuses on the improvement of growth yields of tomato plants and control of Fusarium wilt using inorganic carrier‐based formulations of two fluorescent pseudomonad strains (R62 and R81) and Pi. Methods and Results: The inorganic carrier‐based formulations of pseudomonad strains and Pi were tested for plant growth promotion of tomato plants under glass house and field conditions. In controlled glass house experiments, 8·8‐fold increase in dry root weight and 8·6‐fold increase in dry shoot weight were observed with talcum powder‐based consortium formulation of R81 and Pi. Field trial experiments ascertained the glfass house results with a considerable amount of increase in plant growth responses, and amongst all the treatments, R81 + Pi treatment performed consistently well in field conditions with an increase of 2·6‐, 3·1‐ and 3·9‐fold increase in dry root weight, shoot weight and fruit yield, respectively. The fluorescent pseudomonad R81 and Pi also acted as biocontrol agents, as their treatments could control the incidence of wilt disease caused by Fusarium oxysporum f.sp. lycopersici in tomato plants under glass house conditions. Conclusions: The culture broths of pseudomonads R62, R81 and Pi were successfully used for development of talcum‐ and vermiculite‐based bioinoculant formulations. In controlled glasshouse experiments, the talcum‐based bioinoculant formulations performed significantly better over vermiculite‐based formulations. In field experiments the talcum‐based consortium formulation of pseudomonad R81 and Pi was most effective. Significance and Impact of the Study: This study suggests that the formulations of pseudomonad strains (R62 and R81) and Pi can be used as bioinoculants for improving the productivity of tomato plants. The application of such formulations is a step forward towards sustainable agriculture. 相似文献
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Hidalgo-Carcedo C Hooper S Chaudhry SI Williamson P Harrington K Leitinger B Sahai E 《Nature cell biology》2011,13(1):49-58
Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell-cell junctions. Here we show that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell-cell contact. When actomyosin is not downregulated at cell-cell contacts, migrating cells lose cohesion. We provide a molecular mechanism for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and 'organotypic' models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1-Par3/Par6 complex controls the localization of RhoE to cell-cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell-cell contacts, a loss of cell-cell cohesion and defective collective cell invasion. 相似文献
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