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Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Katherine A. Fitzgerald
Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …
Human Ezrin-Moesin-Radixin Proteins Modulate Hepatitis C Virus Infection, Terence Bukong, Karen Kodys, Gyongyi Szabo
Human Ezrin-Moesin-Radixin Proteins Modulate Hepatitis C Virus Infection, Terence Bukong, Karen Kodys, Gyongyi Szabo
Gyongyi Szabo
Host cytoskeletal proteins of the ezrin-moesin-radixin (EMR) family have been shown to modulate single-stranded RNA virus infection through regulating stable microtubule formation. Antibody engagement of CD81, a key receptor for hepatitis C virus (HCV) entry, induces ezrin phosphorylation. Here we tested the role of EMR proteins in regulating HCV infection and explored potential therapeutic targets. We show that HCV E2 protein induces rapid ezrin phosphorylation and its cellular redistribution with F-actin by way of spleen tyrosine kinase (SYK). Therapeutically blocking the functional roles of SYK or F-actin reorganization significantly reduced Huh7.5 cell susceptibility to HCV J6/JFH-1 infection. Using gene regulation, …
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Gyongyi Szabo
Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …
Integrin (Alpha 6 Beta 4) Regulation Of Eif-4e Activity And Vegf Translation: A Survival Mechanism For Carcinoma Cells, Jun Chung, Robin E. Bachelder, Elizabeth A. Lipscomb, Leslie M. Shaw, Arthur M. Mercurio
Integrin (Alpha 6 Beta 4) Regulation Of Eif-4e Activity And Vegf Translation: A Survival Mechanism For Carcinoma Cells, Jun Chung, Robin E. Bachelder, Elizabeth A. Lipscomb, Leslie M. Shaw, Arthur M. Mercurio
Arthur M. Mercurio
We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the alpha 6 beta 4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells. The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (eIF-4E). The regulation of 4E-BP1 phosphorylation by alpha 6 beta 4 derives from the ability of this integrin to activate the PI-3K-Akt pathway and, consequently, the rapamycin-sensitive kinase mTOR that …
Regulation Of Alpha 6 Beta 1 Integrin Laminin Receptor Function By The Cytoplasmic Domain Of The Alpha 6 Subunit, Leslie M. Shaw, Arthur M. Mercurio
Regulation Of Alpha 6 Beta 1 Integrin Laminin Receptor Function By The Cytoplasmic Domain Of The Alpha 6 Subunit, Leslie M. Shaw, Arthur M. Mercurio
Arthur M. Mercurio
The alpha 6 beta 1 integrin is expressed on the macrophage surface in an inactive state and requires cellular activation with PMA or cytokines to function as a laminin receptor (Shaw, L. M., J. M. Messier, and A. M. Mercurio. 1990. J. Cell Biol. 110:2167-2174). In the present study, the role of the alpha 6 subunit cytoplasmic domain in alpha 6 beta 1 integrin activation was examined. The use of P388D1 cells, an alpha 6-integrin deficient macrophage cell line, facilitated this analysis because expression of either the alpha 6A or alpha 6B subunit cDNAs restores their activation responsive laminin adhesion …
The Activation Dependent Adhesion Of Macrophages To Laminin Involves Cytoskeletal Anchoring And Phosphorylation Of The Alpha 6 Beta 1 Integrin, Leslie M. Shaw, Jeanne M. Messier, Arthur M. Mercurio
The Activation Dependent Adhesion Of Macrophages To Laminin Involves Cytoskeletal Anchoring And Phosphorylation Of The Alpha 6 Beta 1 Integrin, Leslie M. Shaw, Jeanne M. Messier, Arthur M. Mercurio
Arthur M. Mercurio
Macrophages require activation with either PMA (Mercurio, A. M., and L. M. Shaw. 1988. J. Cell Biol. 107:1873-1880) or interferon-gamma (Shaw, L. M., and A. M. Mercurio. 1989. J. Exp. Med. 169:303-308) to adhere to a laminin substratum. In the present study, we identified an integrin laminin receptor on macrophages and characterized cellular changes that occur in response to PMA activation that facilitate laminin adhesion. A monoclonal antibody (GoH3) that recognizes the integrin alpha 6 subunit (Sonnenberg, A., H. Janssen, F. Hogervorst, J. Calafat, and J. Hilgers. 1987. J. Biol. Chem. 262:10376-10383) specifically inhibited adhesion to laminin-coated surfaces. This antibody …
Protein Kinase C-Dependent Mobilization Of The Alpha6beta4 Integrin From Hemidesmosomes And Its Association With Actin-Rich Cell Protrusions Drive The Chemotactic Migration Of Carcinoma Cells, Isaac Rabinovitz, Alex Toker, Arthur M. Mercurio
Protein Kinase C-Dependent Mobilization Of The Alpha6beta4 Integrin From Hemidesmosomes And Its Association With Actin-Rich Cell Protrusions Drive The Chemotactic Migration Of Carcinoma Cells, Isaac Rabinovitz, Alex Toker, Arthur M. Mercurio
Arthur M. Mercurio
We explored the hypothesis that the chemotactic migration of carcinoma cells that assemble hemidesmosomes involves the activation of a signaling pathway that releases the alpha6beta4 integrin from these stable adhesion complexes and promotes its association with F-actin in cell protrusions enabling it to function in migration. Squamous carcinoma-derived A431 cells were used because they express alpha6beta4 and migrate in response to EGF stimulation. Using function-blocking antibodies, we show that the alpha6beta4 integrin participates in EGF-stimulated chemotaxis and is required for lamellae formation on laminin-1. At concentrations of EGF that stimulate A431 chemotaxis ( approximately 1 ng/ml), the alpha6beta4 integrin is …
Pka-Mediated Erk1/2 Inactivation And Hsp70 Gene Expression Following Exercise, C.W. Melling, Matthew Krause, Earl Noble
Pka-Mediated Erk1/2 Inactivation And Hsp70 Gene Expression Following Exercise, C.W. Melling, Matthew Krause, Earl Noble
Jamie Melling
Exercise induces the expression of the cardioprotective protein, Hsp70, through the activation of its transcription factor HSF1. Recently, we reported that administration of a protein kinase A (PKA) inhibitor suppressed exercise-induced hsp70 gene expression, suggesting a role for PKA in the regulation of HSF1 activation in vivo. While the mechanism by which PKA regulates HSF1 is unclear, studies in vitro have reported that HSF1 is phosphorylated on two serine residues by mitogen activated protein kinases (MAPKs); ERK1/2 (ser307) and JNK/SAPK (ser363). As PKA is a regulator of these protein kinases, the current study examined the role of PKA in their …