Project description:Analysis of gene expression profiles of matrix-detached cells with and without expression of ITGB4, in clustering and non-clustering conditions. The experiment tested the hypothesis that the integrin beta 4 (ITGB4) mediates a significant amount of pro-survival signaling in matrix-detached conditions. Expression of ITGB4 in cancer is correlated with poor patient survival and is impliated in increased metastatic spread. Survival in matrix-deprived conditions is essential to metastasis and targeting signaling downstream of the integrin beta 4 may help curtail metasasis.
Project description:Cancer cells acquire anchorage-independence to escape anoikis. This study aimed to evaluate the gene expression signature of SAS cells cultured at the standar plate and the low-attachment plate. Total RNAs were isolated from attached and detached SAS cells, and gene expression signatures were examined using gene expression microarray.
Project description:Reciprocal regulation of integrin-dependent cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases, but remain poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of b1-integrin influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic B1A-K794Q-GFP mutant induced transcriptomic reprograming of embryonic endothelial cells particularly in genes responsible for cell adhesion, proliferation, polarity and barrier function. B1A-K794Q-GFP induced a constitutive activation of MAPK signaling, an impairment of junctions, increased proliferation and an altered contact inhibition at confluency. Structural analysis of integrin b1 interaction with KINDLIN-2, biochemical pulldown assay and molecular dynamic analysis showed that acetylation of K794 increases KINDLIN-2 binding to the integrin b1 cytoplasmic tail. Accordingly, altering KINDLIN-2 levels modified Claudin-5 expression and endothelial barrier function. Revealing how integrin b1 acetylation regulates endothelial cell junctions offers new therapeutic possibilities for controlling vascular permeability.
Project description:Metastasis of cancer cells requires detachment from Extra Cellular Matrix (ECM) to seed cancer cells in a distant organ. Hypoxia is prevalent in this matrix detached cancer cells. Studies have established hypoxia as a chromatin modifier, as it transcriptionally controls expression of various histone demethylases (KDMs); therefore, we hypothesized that the presence of hypoxia could modulate the expression of KDMs in matrix detached cancer cells. Our study showed that in matrix detached cancer cells, both hypoxia and one of the hypoxia regulated H3K27me3 histone demethylase, namely KDM6B, was increased. Simultaneously, we found increased expression of stemness-associated genes, namely SOX-2, SOX-9, and CD44, in hypoxic matrix detached cancer cells. We discovered that KDM6B occupies the promoter region of both SOX-2 and CD44 to regulate their expression epigenetically. Targeting KDM6B reduces its occupancy, thereby expressing the stemness-related genes in matrix detached cancer cells. Further, we noticed increased occupancy of HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in matrix detached cancer cells. This observation was further strengthened as we found a significant positive association between KDM6B and HIF1α in various cancer types. Overall, we found that matrix detachment modulates epigenome by inducing KDM6B activity to regulate the expression of stemness-related genes and hypoxia primarily through HIF1α in matrix detached conditions. KDM6B can be developed as a therapeutic target to eliminate matrix detached cancer cells bound for metastatic events
Project description:Geier2011 - Integrin activation
Rule based model that integrates the available data to test the biololical hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation.
This model is described in the article:
A computational analysis of the dynamic roles of talin, Dok1, and PIPKI for integrin activation.
Geier F, Fengos G, Iber D.
PLoS One. 2011;6(11):e24808.
Abstract:
Integrin signaling regulates cell migration and plays a pivotal role in developmental processes and cancer metastasis. Integrin signaling has been studied extensively and much data is available on pathway components and interactions. Yet the data is fragmented and an integrated model is missing. We use a rule-based modeling approach to integrate available data and test biological hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation. The detailed biochemical characterization of integrin signaling provides us with measured values for most of the kinetics parameters. However, measurements are not fully accurate and the cellular concentrations of signaling proteins are largely unknown and expected to vary substantially across different cellular conditions. By sampling model behaviors over the physiologically realistic parameter range we find that the model exhibits only two different qualitative behaviors and these depend mainly on the relative protein concentrations, which offers a powerful point of control to the cell. Our study highlights the necessity to characterize model behavior not for a single parameter optimum, but to identify parameter sets that characterize different signaling modes.
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Project description:Type-2 innate lymphoid cells (ILC2s) have emerged as key immune-response regulators in renal-inflammatory diseases such as lupus nephritis. However, the adhesion and migration of ILC2s, including in the homeostatic and diseased kidney, are poorly understood. By integrating transcriptomic profiling, flow cytometry, live-cell imaging, and in-vivo models, we showed that renal ILCs are retained in the homeostatic kidney by the adherence of their cell-surface integrin α4β7 to VCAM-1, E-cadherin or fibronectin on structural kidney cells. When cultured on these ligands, ILC2s demonstrated remarkable migration. Knocking down integrin-α4β7 expression reduced ILC2 Areg production. In lupus nephritis, TLR7/9 may downregulate ILC2 expression of integrin-α4β7, thereby both reducing Areg expression and promoting ILC2 egress. Areg loss may promote the proinflammatory-cytokine secretion by T cells. IL-33 upregulated ILC2 integrin-α4β7 and Areg expression. Notably, IL-33 treatment enhanced survival in lupus nephritis by mitigating kidney inflammation. Thus, ILC2 adhesion may be a therapeutic target for autoimmune kidney diseases.
Project description:During senescence of detached rice leaves, tryptophan (Trp) and Trp-derived secondary metabolites such as serotonin and 4-coumaroylserotonin accumulated in concert with methanol (MeOH) production. This senescence-induced MeOH induction was closely associated with levels of pectin methylesterase (PME)1 mRNA and PME enzyme activity. Exogenous challenge of detached rice leaves with 1% MeOH accelerated Trp and serotonin biosynthesis with induction of the corresponding genes. No other solvents including ethanol resulted in a Trp-inducing effect. This MeOH-induced Trp synthesis was positively regulated by abscisic acid but negatively regulated by cytokinin, suggesting hormonal involvement on the action of MeOH. Endogenous overproduction or suppression of MeOH either by PME1 overexpression or RNAi gene silencing revealed that PME1 overexpressing lines produced twofold higher Trp levels with elevated Trp biosynthetic gene expression, whereas RNAi lines showed twofold reduction in Trp level in healthy control rice leaves, suggesting that MeOH acts as an endogenous elicitor to enhance Trp biosynthesis. Among many transcription factors induced following MeOH treatment, the WRKY family showed significant induction patterns of which WRKY14 appeared to play a key regulatory role in MeOH-induced Trp and Trp-derived secondary metabolite biosynthesis. Total RNAs were extracted from the detached rice leaves with 1% MeOH or distilled water for 1 d, and gene expression was compared between the two groups with two replicates. DW, detached leaves in distilled water for 1 day; MeOH (2-replications), methanol treated detached leaves at the same time point as control. 2 sets of separately normalized data; DW-MeOH(1) and MeOH(2).
Project description:Integrins are extracellular matrix receptors comprised of an a and b subunit that connect and mediate signaling between cells and the surrounding matrix. In organogenesis of epithelial tissues, the b1 integrin subunit regulates essential epithelial cell functions, but the role of b1 integrin in epithelial repair is poorly understood. To define the role of b1 integrin during alveolar repair, we challenged b1 integrin deficient mice with intratracheal lipopolysaccharide, resulting in increased mortality with emphysematous lungs 21 days following injury. The alveolar barrier was repopulated with an overabundance of type 2 alveolar epithelial cells, with reduced numbers of elongated alveolar type 1 cells, suggesting b1 integrin is required for type 2 to type 1 epithelial transition. Consistent with this finding, b1 deficient type 2 epithelial cells proliferated at increased rates throughout repair, lacked actin-rich cellular protrusions necessary for lateral cellular extension, and exhibited transcriptomic dysregulation of adherens junction and actin polymerization pathways. Finally, we show that b1 integrin balances actin polymerization versus stabilization through GTPase activation. Taken together, these data support a novel role for b1 integrin in re-establishing the alveolar niche after injury through modulation of type 2 epithelial cell proliferation and cytoskeletal-dependent cell shape change.
Project description:To elucidate the mechanisms and down-stream pathways affected by activated integrin expression, we performed transcriptomic analyses of dorsal root gangliona (DRG) sensory neurons transduced with α9 integrin and its activator kindlin-1(α9k1), which enable axons to interact with tenascin-C, or controls, with and without dorsal root/central axotomy.
Project description:Macrophages infiltrate the infarcted heart and play a critical role in repair, remodeling and fibrosis. Macrophages sense changes in the extracellular matrix (ECM) environment through Integrins, thus activating signaling pathways that regulate their function. Analysis of our previous RNA sequencing data identified integrin α5 (Itgα5) as one of the most upregulated integrin genes in infarct macrophages. Accordingly, we hypothesized that integrin α5 signaling in infarct macrophages transduces ECM-derived signals, regulating responses critical for repair and remodeling of the infarcted heart.