Biochemistry, Biophysics, and Structural Biology | Open Access Articles

Endoplasmic Reticulum Stress-Induced Hepatocellular Death Pathways Mediate Liver Injury And Fibrosis Via Stimulator Of Interferon Genes., Arvin Iracheta-Vellve, Jan Petrasek, Benedek Gyongyosi, Abhishek Satishchandran, Patrick Lowe, Karen Kodys, Donna Catalano, Charles D. Calenda, Evelyn A. Kurt-Jones, Kate A. Fitzgerald, Gyongyi Szabo

Katherine A. Fitzgerald

Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon Regulatory Factor 3 (IRF3) regulates hepatocyte apoptosis and production of Type-I interferons (IFNs). In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the ER adapter, Stimulator of Interferon Genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically-induced liver fibrogenesis. To test this, we performed acute or chronic carbontetrachloride (CCl4) administration to WT, …

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Endoplasmic Reticulum Stress-Induced Hepatocellular Death Pathways Mediate Liver Injury And Fibrosis Via Stimulator Of Interferon Genes., Arvin Iracheta-Vellve, Jan Petrasek, Benedek Gyongyosi, Abhishek Satishchandran, Patrick Lowe, Karen Kodys, Donna Catalano, Charles D. Calenda, Evelyn A. Kurt-Jones, Kate A. Fitzgerald, Gyongyi Szabo

Gyongyi Szabo

Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon Regulatory Factor 3 (IRF3) regulates hepatocyte apoptosis and production of Type-I interferons (IFNs). In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the ER adapter, Stimulator of Interferon Genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically-induced liver fibrogenesis. To test this, we performed acute or chronic carbontetrachloride (CCl4) administration to WT, …

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Stat6 Mediates Interleukin-4 Growth Inhibition In Human Breast Cancer Cells, Jennifer L. Gooch, B. Christy, D. Yee

Jennifer L. Gooch

In addition to acting as a hematopoietic growth factor, interleukin-4 (IL-4) inhibits growth of some transformed cells in vitro and in vivo. In this study, we show that insulin receptor substrate (IRS)-1, IRS-2, and signal transducer and activator of transcription 6 (STAT6) are phosphorylated following IL-4 treatment in MCF-7 breast cancer cells. STAT6 DNA binding is enhanced by IL-4 treatment. STAT6 activation occurs even after IRS-1 depletion, suggesting the two pathways are independent. To examine the role of STAT6 in IL-4-mediated growth inhibition and apoptosis, a full-length STAT6 cDNA was transfected into MCF-7 cells. Transient overexpression of STAT6 resulted in …

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Nuclear Pore Component Nup98 Is A Potential Tumor Suppressor And Regulates Posttranscriptional Expression Of Select P53 Target Genes, Stephan Singer, Ruiying Zhao, Anthony M. Barsotti, Anette Ouwehand, Mina Fazollahi, Elias Coutavas, Kai Breuhahn, Olaf Neumann, Thomas Longerich, Tobias Pusterla, Maureen A. Powers, Keith M. Giles, Peter J. Leedman, Jochen Hess, David Grunwald, Harmen J. Bussemaker, Robert H. Singer, Peter Schirmacher, Carol Prives

David Grünwald

The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3sigma) to be similarly regulated by Nup98. The expression …

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Effects Of Canola And Corn Oil Mimetic On Jurkat Cells, Gabriela Ion, Kayla Fazio, Juliana A. Akinsete, W. Elaine Hardman

Gabriela Ion

BACKGROUND: The Western diet is high in omega-6 fatty acids and low in omega-3 fatty acids. Canola oil contains a healthier omega 3 to omega 6 ratio than corn oil. Jurkat T leukemia cells were treated with free fatty acids mixtures in ratios mimicking that found in commercially available canola oil (7% α-linolenic, 30% linoleic, 54% oleic) or corn oil (59% linoleic, 24% oleic) to determine the cell survival or cell death and changes in expression levels of inflammatory cytokines and receptors following oil treatment. METHODS: Fatty acid uptake was assessed by gas chromatography. Cell survival and cell death were …

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Effects Of Canola And Corn Oil Mimetic On Jurkat Cells, Gabriela Ion, Kayla Fazio, Juliana A. Akinsete, W. Elaine Hardman

Elaine Hardman Ph.D.

BACKGROUND: The Western diet is high in omega-6 fatty acids and low in omega-3 fatty acids. Canola oil contains a healthier omega 3 to omega 6 ratio than corn oil. Jurkat T leukemia cells were treated with free fatty acids mixtures in ratios mimicking that found in commercially available canola oil (7% α-linolenic, 30% linoleic, 54% oleic) or corn oil (59% linoleic, 24% oleic) to determine the cell survival or cell death and changes in expression levels of inflammatory cytokines and receptors following oil treatment. METHODS: Fatty acid uptake was assessed by gas chromatography. Cell survival and cell death were …

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Consumption Of High Ω-3 Fatty Acid Diet Suppressed Prostate Tumorigenesis In C3(1) Tag Mice, Juliana A. Akinsete, Gabriela Ion, Theodore R. Witte, W. Elaine Hardman

Elaine Hardman Ph.D.

Prostate cancer incidence and mortality are high in the Western world and high ω-6/ω-3 PUFA in the Western diet may be a contributing factor. We investigated whether changing from a diet that approximates ω-6 fat content of the Western diet to a high ω-3 fat diet at adulthood might reduce prostate cancer risk. Female SV 129 mice that had consumed a high ω-6 diet containing corn oil for 2 weeks were bred with homozygous C3(1)Tag transgenic male mice. All male offspring were weaned to the corn oil diet (CO) until postpuberty when half of the male offspring were transferred to …

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Retinoic Acid Decreases Atf-2 Phosphorylation And Sensitizes Melanoma Cells To Taxol-Mediated Growth Inhibition, Ying Huang, Jennifer Minigh, Sarah Miles, Richard N. Niles

Richard M. Niles

Cutaneous melanoma is often resistant to chemo- and radiotherapy. This resistance has recently been demonstrated to be due, at least in part, to high activating transcription factor 2 (ATF-2) activity in these tumors. In concordance with these reports, we found that B16 mouse melanoma cells had higher levels of ATF-2 than immortalized, but non-malignant mouse melanocytes. In addition, the melanoma cells had a much higher amount of phosphorylated (active) ATF-2 than the immortalized melanocytes. In the course of determining how retinoic acid (RA) stimulates activating protein-1 (AP-1) activity in B16 melanoma, we discovered that this retinoid decreased the phosphorylation of …

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Therapeutic Targeting Of C-Terminal Binding Protein In Human Cancer, Michael W. Straza, Seema Paliwal, Ramesh C. Kovi, Barur R. Rajeshkumar, Peter Trenh, Daniel Parker, Giles F. Whalen, Stephen Lyle, Celia A. Schiffer, Steven R. Grossman

Celia A. Schiffer

The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable …

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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Katherine A. Fitzgerald

Gyongyi Szabo

Stat6 Mediates Interleukin-4 Growth Inhibition In Human Breast Cancer Cells, Jennifer L. Gooch, B. Christy, D. Yee

Jennifer L. Gooch

David Grünwald

Effects Of Canola And Corn Oil Mimetic On Jurkat Cells, Gabriela Ion, Kayla Fazio, Juliana A. Akinsete, W. Elaine Hardman

Gabriela Ion

Effects Of Canola And Corn Oil Mimetic On Jurkat Cells, Gabriela Ion, Kayla Fazio, Juliana A. Akinsete, W. Elaine Hardman

Elaine Hardman Ph.D.

Consumption Of High Ω-3 Fatty Acid Diet Suppressed Prostate Tumorigenesis In C3(1) Tag Mice, Juliana A. Akinsete, Gabriela Ion, Theodore R. Witte, W. Elaine Hardman

Elaine Hardman Ph.D.

Retinoic Acid Decreases Atf-2 Phosphorylation And Sensitizes Melanoma Cells To Taxol-Mediated Growth Inhibition, Ying Huang, Jennifer Minigh, Sarah Miles, Richard N. Niles

Richard M. Niles

Therapeutic Targeting Of C-Terminal Binding Protein In Human Cancer, Michael W. Straza, Seema Paliwal, Ramesh C. Kovi, Barur R. Rajeshkumar, Peter Trenh, Daniel Parker, Giles F. Whalen, Stephen Lyle, Celia A. Schiffer, Steven R. Grossman

Celia A. Schiffer