Biomedical subjects

Angels Navarro

Publications and source records attributed to Angels Navarro.

4 recordsLinked to original sources

PubMed2004

A role for caveolae in cell migration.

Caveolae are specialized plasma membrane subdomains capable of transport and sophisticated compartmentalization of cell signaling. Numerous cell functions, including cell type-specific functions, involve caveolae and require caveolin-1, the major protein component of these organelles. Caveolae are particularly abundant in endothelial cells and participate in endothelial transcytosis, vascular permeability, vasomotor tone control, and vascular reactivity. Caveolin-1 drives the formation of plasma membrane caveolae and anchors them to the actin cytoskeleton, modulates cell interaction with the extracellular matrix, pulls together and regulates signaling molecules, and transports cholesterol. Via these functions, caveolin-1 might play an important role in cell movement through control of cell membrane composition and membrane surface expansion, polarization of signaling molecules and matrix proteolysis, and/or cytoskeleton remodeling. Caveolae and caveolin-1 are polarized in migrating endothelial cells, indicating they may play a role in cell motility. Several studies have shown that manipulation of caveolin-1 expression affects cell migration in a complex way. We are reviewing the current data and hypotheses in favor of an essential role for caveolae in cell migration.

Animals↗

PubMed2003

Cells previously desensitized to type 1 interferons display different mechanisms of activation of stat-dependent gene expression from naïve cells.

Over the past decade, a wealth of knowledge has been obtained concerning the mechanisms by which interferons (IFNs) and other cytokines activate or down-regulate immediate early genes via the Jak/Stat pathway. In contrast, little information is available on interferon-activated gene expression in naïve cells compared with cells that have been desensitized and subsequently resensitized to the actions of these cytokines. In naïve cells, the ISG54 gene is activated via IFN beta-stimulated formation of ISGF3, a heterotrimeric DNA binding complex consisting of p48 (IRF9) and tyrosine-phosphorylated Stat1 and Stat2. In contrast, in previously desensitized cells IFN beta weakly stimulates the assembly of an ISGF3-like complex that lacks Stat1, even though ISG54 mRNA induction is the same as in naïve cells. The lack of Stat1 tyrosine phosphorylation and DNA binding is due to increased activity of a protein-tyrosine phosphatase. In cells that do not express the tyrosine phosphatase Tc-PTP, the rate of Stat1 dephosphorylation is the same in naïve and previously desensitized cells. These results implicate Tc-PTP in a novel role in the regulation of type 1 interferon-stimulated gene expression.

Animals↗

PubMed2003

Thrombomodulin RNA is destabilized through its 3'-untranslated element in cells exposed to IFN-gamma.

Interferon-gamma (IFN-gamma) is a potent activator of mononuclear phagocytes, allowing them to play a prominent role in acute and chronic inflammatory responses. IFN-gamma binding to its cell surface receptor initiates changes in the steady-state levels of cellular RNAs, permitting the proteins encoded by these RNAs to exert its biologic actions. Hundreds of cellular RNAs have been identified whose rates of transcription are altered by incubation of cells with IFNs. The rates of transcription of many of the genes encoding these RNAs are enhanced by IFN-gamma-mediated activation of the Stat1 transcription factor that is tyrosine phosphorylated and translocates to the nucleus, where it binds enhancers present in IFN-stimulated genes (ISGs). IFN-gamma can also modify the concentrations of some RNAs by posttranscriptional mechanisms. However, very little is understood about the molecular mechanisms regulating this phenomenon. We have identified the RNA encoding thrombomodulin (TM), a physiologic receptor for thrombin, that is downregulated in primary human monocytes incubated with IFN-gamma. Using actinomycin D as a transcriptional inhibitor, we show that the mRNA half-life is rapidly shortened by IFN-gamma. The TM transcript contains a large 3'-untranslated region (UTR), with several AU-rich elements (AREs), elements that have been implicated in the regulation of mRNA decay. Using a tetracycline-regulatory promoter system, we analyzed RNA levels in the absence of transcription of TM. Results from these experiments indicate that incubation of cells with IFN-gamma accelerates the decay of TM RNA through its 3'-UTR. This is the first report describing a clear posttranscriptional downregulation of an mRNA by IFN-gamma that identifies the 3'-UTR as a target of IFN-gamma-stimulated destabilization.

3' Untranslated Regions↗

PubMed2003

A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion.

Type I interferon (IFN)-alpha/beta and type II IFN-gamma induce the expression of early response genes through activation of the Janus tyrosine kinase/signal transducer and activator of transcription (Stat) pathway. Although IFNs regulate a variety of other signaling cascades, little is known about how they contribute to the biological activities of these cytokines. In this study, we demonstrate that IFN-beta or IFN-gamma induces the phosphorylation of the serine/threonine kinase Akt in primary human peripheral blood monocytes. Abrogation of the IFN-stimulated Akt activation by phosphatidylinositol-3 kinase (PI-3K) inhibitors prevents IFN-induced adhesion in these cells, and IFN activation of the Stat1-dependent guanylate-binding protein (GBP) gene is not affected. Importantly, Stat1-deficient bone marrow macrophages displayed a similar level of IFN-gamma-stimulated adhesion compared with macrophages derived from wild-type littermates. These findings demonstrate for the first time that IFN stimulation of a PI-3K signaling cascade modulates the ability of these cytokines to regulate monocyte adhesion, and this process does not require the expression of Stat1, a primary mediator of IFN-gamma signaling.

Animals↗