190 research outputs found
Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination
No full textThe process of metastasis is complex1. In breast cancer, there are frequently long time intervals between cells leaving the primary tumour and growth of overt metastases2,3. Reasons for disease indolence and subsequent transition back to aggressive growth include interactions with myeloid and fibroblastic cells in the tumour microenvironment and ongoing immune surveillance4-6. However, the signals that cause actively growing cells to enter an indolent state, thereby enabling them to survive for extended periods of time, are not well understood. Here we reveal how the behaviour of indolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, in particular alveolar type 1 cells. This promotes the formation of fibronectin fibrils by indolent cells that drive integrin-dependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified secreted frizzled-related protein 2 (SFRP2) as a key mediator of this interaction. Sfrp2 is induced in breast cancer cells by signals from lung epithelial cells and promotes fibronectin fibril formation and survival, whereas blockade of Sfrp2 expression reduces the burden of indolent disease
Phosphorylation of the RNA binding protein Zfs1 modulates sexual differentiation in fission yeast
No full textSexual differentiation in the fission yeast Schizosaccharomyces pombe promotes cell cycle arrest and extensive changes in gene expression, resulting in cell-to-cell fusion, the exchange of hereditary material, and specialized cell division. These events are detrimental to the cell if they are triggered in inappropriate conditions, and therefore the decision to differentiate must be precisely controlled. Here, we investigated the role of the RNA-binding protein Zfs1 in this process by identifying its targets and characterizing novel posttranslational regulation. We found that Zfs1 negatively regulates the G1 cyclin Puc1, and deregulated Puc1 levels inhibit differentiation in the zfs1Δ mutant. We also found that Zfs1 undergoes phosphorylation, which is stimulated by nitrogen depletion or inhibition of the TOR pathway. Phosphorylation of Zfs1 modulates Puc1 accumulation and plays an important role in the cell's response to sexual differentiation signals. We propose that Zfs1 functions as an integrator of nutrient information to modulate sexual differentiation, contributing to the establishment of the differentiation-activating threshold.</jats:p
Transcriptional targets of Eph receptor and ephrin signalling in the zebrafish hindbrain
No full textPhosphorylation of the RNA binding protein Zfs1 modulates sexual differentiation in fission yeast
No full textSexual differentiation in the fission yeast Schizosaccharomyces pombe promotes cell cycle arrest and extensive changes in gene expression, resulting in cell-to-cell fusion, the exchange of hereditary material and specialized cell division. These events are detrimental to the cell if they are triggered in inappropriate conditions, and therefore the decision to differentiate must be precisely controlled. Here, we investigated the role of the RNA-binding protein Zfs1 in this process by identifying its targets and characterizing novel post-translational regulatory mechanisms. We found that Zfs1 negatively regulates the G1 cyclin Puc1, and deregulated Puc1 levels inhibit differentiation in the zfs1Δ mutant. We also found that Zfs1 undergoes phosphorylation, which is stimulated upon nitrogen depletion or inhibition of the TOR pathway. Phosphorylation of Zfs1 modulates accumulation of Puc1 and plays an important role in the response of the cell to sexual differentiation signals. We propose that Zfs1 functions as an integrator of nutrient information to modulate sexual differentiation, contributing to the establishment of the differentiation-activating threshold
Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
No full textMetastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse
Increased Skin Papilloma Formation in Mice Lacking Glutathione Transferase GSTP
No full textThe glutathione S-transferase GSTP is overexpressed in many human cancers and chemotherapy-resistant cancer cells, where there is evidence that GSTP may have additional functions beyond its known catalytic role. On the basis of evidence that Gstp-deficient mice have a comparatively higher susceptibility to skin carcinogenesis, we investigated whether this phenotype reflected an alteration in carcinogen detoxification or not. For this study, Gstp(-/-) mice were interbred with Tg.AC mice that harbor initiating H-ras mutations in the skin. Gstp(-/-)/Tg.AC mice exposed to the proinflammatory phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) exhibited higher tumor incidence and multiplicity with a significant thickening of skin after treatment, illustrating hyperproliferative growth. Unexpectedly, we observed no difference in cellular proliferation or apoptosis or in markers of oxidative stress, although higher levels of the inflammatory marker nitrotyrosine were found in Gstp(-/-)/Tg.AC mice. Instead, gene set enrichment analysis of microarray expression data obtained from skin revealed a more proapoptotic and proinflammatory environment shortly after TPA treatment. Within 4 weeks of TPA treatment, Gstp(-/-)/Tg.AC mice displayed altered lipid/sterol metabolism and Wnt signaling along with aberrant processes of cytoskeletal control and epidermal morphogenesis at both early and late times. In extending the evidence that GSTP has a vital role in normal homeostatic control and cancer prevention, they also strongly encourage the emerging concept that GSTP is a major determinant of the proinflammatory character of the tumor microenvironment. This study shows that the GSTP plays a major role in carcinogenesis distinct from its role in detoxification and provides evidence that the enzyme is a key determinant of the proinflammatory tumor environment. Cancer Res; 71(22); 7048-60. (C)2011 AACR.</p
Supplementary Figure 2 from An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells
No full textSupplementary Figure 2 from An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cell
Supplementary Figure 1 from An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells
No full textSupplementary Figure 1 from An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cell
Proteome-wide identification and quantification of S-glutathionylation targets in mouse liver
No full textProtein S-glutathionylation is a reversible post-translational modification regulating sulfhydryl homeostasis. However, little is known about the proteins and pathways regulated by S-glutathionylation in whole organisms and current approaches lack the sensitivity to examine this modification under basal conditions. We now report the quantification and identification of S-glutathionylated proteins from animal tissue, using a highly sensitive methodology combining high-accuracy proteomics with tandem mass tagging to provide precise, extensive coverage of S-glutathionylated targets in mouse liver. Critically, we show significant enrichment of S-glutathionylated mitochondrial and Krebs cycle proteins, identifying that S-glutathionylation is heavily involved in energy metabolism processes in vivo. Furthermore, using mice nulled for glutathione S-transferase Pi (GSTP) we address the potential for S-glutathionylation to be mediated enzymatically. The data demonstrate the impact of S-glutathionylation in cellular homeostasis, particularly in relation to energy regulation and is of significant interest for those wishing to examine S-glutathionylation in an animal model.</p
Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPARγ agonists: evidence for disparate functional effects which are independent of NF-κB and PPARγ
No full textLigands of peroxisome proliferator-activated receptor-γ (PPARγ) are thought to possess anti-inflammatory properties mediated via both PPARγ dependent and independent mechanisms. This work investigates the effects of PPARγ ligands on the regulation of cyclooxygenase-2 (COX-2) in the human lung epithelial cell line, A549. The synthetic ligand troglitazone activated the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase pathway (MAPK), whereas the endogenous ligand, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), only activated the PI3K pathway. 15d-PGJ2 had no detectable effects on COX-2, mPGES expression, or PGE2 production. However, troglitazone induced time-dependent COX-2 expression, which was insensitive to PPARγ antagonists, but was abrogated by inhibitors of PI3K and the ERK MAP kinase pathway. Furthermore, troglitazone induced mPGES expression and PGE2 production. Neither troglitazone nor 15d-PGJ2 was able to convincingly activate NF-κB in A549 cells. Further heterogeneity in the responses to troglitazone and 15d-PGJ2 was observed in the regulation of gene expression as assessed by microarray analysis. In summary, this study provides compelling evidence that troglitazone (like 15d-PGJ2) can exert functional effects independently of actions via PPARγ. Moreover, we have identified unique biochemical and functional actions of troglitazone that are not shared by 15d-PGJ2, which may influence the therapeutic potential of this compound in inflammatory settings
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