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Results for “Cell Migration Inhibition”

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At least 55 records · Page 3Linked to original sources
PubMed2006

Caspase proteolysis of the integrin beta4 subunit disrupts hemidesmosome assembly, promotes apoptosis, and inhibits cell migration.

Caspases are a conserved family of cell death proteases that cleave intracellular substrates at Asp residues to modify their function and promote apoptosis. In this report we identify the integrin beta4 subunit as a novel caspase substrate using an expression cloning strategy. Together with its alpha6 partner, alpha6beta4 integrin anchors epithelial cells to the basement membrane at specialized adhesive structures known as hemidesmosomes and plays a critical role in diverse epithelial cell functions including cell survival and migration. We show that integrin beta4 is cleaved by caspase-3 and -7 at a conserved Asp residue (Asp(1109)) in vitro and in epithelial cells undergoing apoptosis, resulting in the removal of most of its cytoplasmic tail. Caspase cleavage of integrin beta4 produces two products, 1) a carboxyl-terminal product that is unstable and rapidly degraded by the proteasome and 2) an amino-terminal cleavage product (amino acids 1-1109) that is unable to assemble into mature hemidesmosomes. We also demonstrate that caspase cleavage of integrin beta4 sensitizes epithelial cells to apoptosis and inhibits cell migration. Taken together, we have identified a previously unrecognized proteolytic truncation of integrin beta4 generated by caspases that disrupts key structural and functional properties of epithelial cells and promotes apoptosis.

Apoptosis↗
PubMed1996

Exposure of periodontal ligament cells to methyl mercaptan reduces intracellular pH and inhibits cell migration.

Volatile sulfur compounds such as hydrogen sulfide and methyl mercaptan have been associated with adult periodontitis as well as with healing surgical wounds. To examine the effects of these compounds on the periodontium, we assayed periodontal ligament (PDL) cells for changes in intracellular pH, total protein, and cell migration following chronic exposure to CH3SH. Intracellular pH was quantitated by fluorescence measurements of cells loaded with BCECF, a pH-sensitive dye. Data show that 48-hour exposure to mercaptan lowered resting intracellular pH but did not consistently alter activity of the Na/H exchanger. This effect was seen in PDL cells from three different patients. Lowered pH was accompanied by decreases in both total protein and mature alpha 1 and alpha 2 chains of type I collagen. Since reductions in intracellular pH and total protein have been associated with inhibition of cell motility, migration was quantitated by sequential computer imaging, which measured the increase in size of plated cell circles at different times of migration. Incubation of PDL cells in pH 7.4 and 6.6 buffers reversibly altered intracellular pH. Migration was reversibly inhibited in pH 6.8 buffer. Exposure to CH3SH reduced intracellular pH in pH 7.4 buffer and in three independent assays inhibited enlargement of cell circles in pH 7.4 medium. These effects were therefore not related to alterations of extracellular pH, which remained at 7.4. The results support the hypothesis that gases such as methyl mercaptan may play a role in both surgical wound healing and periodontal disease by adversely affecting cell function and suggest that alterations in intracellular pH may be part of the mechanism for these changes.

Analysis of Variance↗
PubMed1977

In vitro correlate of tranplantation immunity: spleen cell migration inhibition in the lizard, Calotes Versicolor.

Sensitization to skin allografts in the lizard, Calotes versicolor, was assessed using the in vitro capillary migration inhibition (MI) assay. In the presence of the respective donor antigen, an appreciable degree of MI of sensitized spleen cells was observed as early as 4 days after grafting. A maximum level was attained on day 7 and this response was maintained as long as one month after grafting with only slight fluctuations in the level of MI. When the clinical manifestations of graft rejection culminated on day 35, the degree of MI was still at the maximum level. MI of allograft-sensitized spleen cells is an antigen specific event, and the same level of inhibition is observed whether the specific antigen is provided in the form of intact spleen cells or spleen extract.

Animals↗
PubMed1999

Estrogen receptor-alpha gene transfer into bovine aortic endothelial cells induces eNOS gene expression and inhibits cell migration.

OBJECTIVES: It has been suggested that estrogen may improve endothelial cell function to delay the onset of atherosclerosis in pre-menopausal females, though its mechanism of action is not fully understood. We examined the hypothesis that human estrogen receptor-alpha (ER alpha) gene transfection improves the endothelial cell function. METHODS: A replication deficient adenoviral vector was used to transfect the ER alpha gene into bovine aortic endothelial cells (BAEC) and a GFP gene containing vector was used as control. Expression of the eNOS gene was determined by Northern blot analysis and enzyme activity assay; cell migration was assayed using a Transwell apparatus; and tyrosine phosphorylation of FAK was estimated by Western blot analysis. RESULTS: ER alpha gene transfection of endothelial cells produced a 2-3-fold increase in eNOS mRNA and protein levels as well as a significant increase (P < 0.05) in NOS activity as measured by citrulline assay and nitrite accumulation in the media in response to bradykinin stimulation. Treatment of cells with estrogen blocking agent ICI 182780 inhibited eNOS induction in response to ER alpha transfection. ER alpha gene transfection significantly inhibited (P < 0.05) bFGF-induced chemotactic migration of endothelial cells but increased cell attachment to fibronectin, laminin, and type I and IV collagens. ER alpha gene transfer also inhibited bFGF-stimulated tyrosine phosphorylation of FAK. CONCLUSION: Our results suggest that the atheroprotective effects of estrogen may in part be mediated by ER alpha-induced upregulation of eNOS gene expression and maintenance of endothelial cell function and integrity.

Animals↗
PubMed2006

Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity.

Plexins are cell surface receptors for semaphorins and regulate cell migration in many cell types. We recently reported that the semaphorin 4D (Sema4D) receptor Plexin-B1 functions as a GTPase-activating protein (GAP) for R-Ras, a member of Ras family GTPases implicated in regulation of integrin activity and cell migration. We characterized the role of R-Ras downstream of Sema4D/Plexin-B1 in cell migration. Activation of Plexin-B1 by Sema4D suppressed the ECM-dependent R-Ras activation, R-Ras-mediated phosphatydylinositol 3-kinase activation, and beta(1) integrin activation through its R-Ras GAP domain, leading to inhibition of cell migration. In addition, inactivation of R-Ras by overexpression of the R-Ras-specific GAP or knockdown of R-Ras by RNA interference was sufficient for suppressing beta(1) integrin activation and cell migration in response to the ECM stimulation. Thus, we conclude that R-Ras activity is critical for ECM-mediated beta(1) integrin activation and cell migration and that inactivation of R-Ras by Sema4D/Plexin-B1-mediated R-Ras GAP activity controls cell migration by modulating the activity of beta(1) integrins.

Animals↗
PubMed2006

Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing.

BACKGROUND & AIMS: Muc3 intestinal mucin contains an extracellular cysteine-rich domain with 2 epidermal growth factor (EGF)-like motifs. The aim of this study was to determine the functional properties of Muc3 proteins. METHODS: Glutathione S-transferase-fusion proteins containing both Muc3 EGF-like domains (m3EGF1,2) or truncated versions (m3EGF1 and m3EGF2) were purified from Escherichia coli. Mouse colon (young adult mouse colon) and human A431 and LoVo cells were examined for migration and tyrosine phosphorylation in response to recombinant proteins. LoVo cells were transfected with a human MUC3A transmembrane-EGF1,2 construct and a stable clone was isolated (LhM3c14). Endogenous MUC3A in LoVo was inhibited by specific small interfering RNA transfection. Apoptosis was quantitated by nuclear morphology or terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling assay. Colitis was induced in mice by oral 5% dextran sodium sulfate or rectal 5% acetic acid, followed by enema treatments. RESULTS: m3EGF1,2 stimulated cell migration in all cell lines, but did not induce proliferation. Migration was inhibited by a tyrosine phosphorylation inhibitor, genistein, but not by the EGF receptor inhibitor, tyrphostin (AG1478). Inhibition of endogenous MUC3A in LoVo reduced baseline migration. Tyrosine phosphorylation of ErbB receptors was not observed after treatment of cells with m3EGF1,2. LoVo cells pretreated with m3EGF1,2 and transfected LhM3c14 cells showed reduced apoptosis in response to tumor necrosis factor alpha or Fas-receptor stimulation. Administration of m3EGF1,2 per rectum significantly reduced mucosal ulceration and apoptosis in experimental acute colitis. Truncated proteins m3EGF1 and m3EGF2 had no effect. CONCLUSIONS: The Muc3 mucin cysteine-rich domain plays an active role in epithelial restitution, and represents a potential novel therapeutic agent for intestinal wound healing.

Amino Acid Sequence↗