Open Access Published by De Gruyter Open Access

Volume 3 Issue 1

January 2016

Issue of Cell Pathology

Contents
Journal Overview

Open Access February 11, 2016

Inhibition of IRE1 signaling affects expression of a subset genes encoding for TNF-related factors and receptors and modifies their hypoxic regulation in U87 glioma cells

Oleksandr H. Minchenko, Iryna V. Kryvdiuk, Dmytro O. Minchenko, Olena O. Riabovol, Oleh V. Halkin

Page range: 1-15

More Download PDF

Abstract

Inhibition of IRE1 (inositol requiring enzyme-1), the major signaling pathway of endoplasmic reticulum stress, significantly decreases tumor growth and proliferation of glioma cells. To elucidate the role of IRE1- mediated glioma growth, we studied the expression of a subset genes encoding for TNF (tumor necrosis factor)- related factors and receptors and their hypoxic regulation in U87 glioma cells overexpressing dominant-negative IRE1 (dnIRE1). We demonstrated that the expression of TNFAIP1, TNFRSF10D, TNFRSF21, TNFRSF11B, TNFSF7, and LITAF genes is increased in glioma cells with modified IRE1; however, TNFRSF10B, TRADD, and TNFAIP3 is down-regulated in these cells as compared to their control counterparts. We did not find TNFRSF1A gene expression to change significantly under this experimental condition. In control glioma cells, hypoxia leads to the up-regulated expression of TNFAIP1, TNFAIP3, TRADD, and TNFRSF10D genes and the concomitant down-regulation of TNFRSF21, TNFRSF11B, and LITAF genes; while, TNFRSF10B and TNFRSF1A genes are resistant to hypoxic treatment. However, inhibition of IRE1 modifies the hypoxic regulation of LITAF, TNFRSF21, TNFRSF11B, and TRADD genes and introduces hypoxia-induced sensitivity to TNFRSF10B, TNFRSF1A, and TNFSF7 gene expressions. Furthermore, knockdown by siRNA of TNFRSF21 mRNA modifies the hypoxic effect on the IRE1-dependent rate of proliferation and cell death in U87 glioma cells. The present study demonstrates that fine-tuned manipulation of the expression of TNF-related factors and receptors directly relating to cell death and proliferation, is mediated by an effector of endoplasmic reticulum stress, IRE1, as well as by hypoxia in a gene-specific manner. Thus, inhibition of the kinase and endoribonuclease activities of IRE1 correlates with deregulation of TNF-related factors and receptors in a manner that is gene specific and thus slows tumor growth.

Open Access May 27, 2016

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

Martina Korfei, Clemens Ruppert, Benjamin Loeh, Poornima Mahavadi, Andreas Guenther

Page range: 16-49

More Download PDF

Abstract

The activation of Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) was first observed in patients with familial interstitial pneumonia (FIP) carrying mutations in the C-terminal BRICHOS domain of surfactant protein C (SFTPC). Here, aggresome formation and severe ER stress was demonstrated in type-II alveolar epithelial cells (AECII), which specifically express this very hydrophobic surfactant protein. In subsequent studies, FIP-patients with mutations in the gene encoding surfactant protein A2 (SFTPA2) were discovered, whose overexpression in epithelial cells in vitro also resulted in significant induction of ER stress. Moreover, prominent ER stress in AECII was also observed in FIP-patients not carrying the SFTPC/SFTPA2 mutations, as well as in patients with the more common sporadic forms of IP. Additionally, cases of adult-onset FIP with mutations in Telomerase genes and other telomereassociated components were reported. These mutations were associated with telomere shortening, which is a potential cause for triggering a persistent DNA damage response and replicative senescence in affected cells. Moreover, shortened telomeres were observed directly in the AECII of FIP-patients, and even sporadic IP cases, in the absence of any gene mutations. Here, we try to figure out the possible origins of ER stress in sporadic IP cases and non-SFTPC/SFTPA2-associated FIP.

Open Access July 19, 2016

IRE-1α regulates expression of ubiquitin specific peptidases during hypoxic response in U87 glioma cells

Oleksandr H. Minchenko, Dariia O. Tsymbal, Dmytro O. Minchenko, Olena O. Riabovol, Oleh V. Halkin, Oksana O. Ratushna

Page range: 50-62

More Download PDF

Abstract

IRE-1α (inositol requiring enzyme-1α), the most evolutionarily conserved of the endoplasmic reticulum stress signaling pathways, is highly implicated in sustaining the proliferation of glioma cells and subsequent tumor growth, which is decreased by the inhibition of IRE-1α. To explore the IRE-1α mediated regulation of ubiquitin system in glioma cells, the expression of a subset of ubiquitin specific peptidases (USP) and of ubiquitin activating enzyme E1-like protein/autophagy related 7 (GSA7/ATG7) genes was studied, during hypoxic stress in wild type and U87 glioma cells with inhibited IRE-1α. Hypoxic treatment of wild type glioma cells leads to the up-regulation of USP25 and the concomitant downregulation of USP1, USP10, USP14, and GSA7 genes. USP4 and USP22 genes expression did not significantly change with hypoxic treatment. Inhibition of IRE-1α activity led to up-regulation of USP1, USP4, USP10, USP22, and USP25, while USP14 and GSA7 genes were down-regulated. Therefore, IRE-1α activity modifies substrate-targeting specificity to proteasome during hypoxic stress, which in turn can affect cell survival. Inhibition of IRE-1α correlates directly with deregulation of ubiquitin specific peptidases and GSA7 in a fashion that ultimately slows tumor growth.

Open Access September 19, 2016

α1-antitrypsin Deficiency: A Misfolded Secretory Protein Variant with Unique Effects on the Endoplasmic Reticulum

David H Perlmutter

Page range: 63-72

More Download PDF

Abstract

In the classical form of α1-antitrypsin deficiency (ATD) a point mutation leads to accumulation of a misfolded secretory glycoprotein in the endoplasmic reticulum (ER) of liver cells and so ATD has come to be considered a prototypical ER storage disease . It is associated with two major types of clinical disorders, chronic obstructive pulmonary disease (COPD) by lossof- function mechanisms and hepatic cirrhosis and carcinogenesis by gain-of-function mechanisms. The lung disease predominantly results from proteolytic damage to the pulmonary connective tissue matrix because of reduced levels of protease inhibitor activity of α1-anitrypsin (AT) in the circulating blood and body fluids. Cigarette smoking is a powerful disease-promoting modifier but other modifiers are known to exist because variation in the lung disease phenotype is still found in smoking and non-smoking homozygotes. The liver disease is highly likely to be caused by the proteotoxic effects of intracellular misfolded protein accumulation and a high degree of variation in the hepatic phenotype among affected homozygotes has been hypothetically attributed to genetic and environmental modifiers that alter proteostasis responses. Liver biopsies of homozygotes show intrahepatocytic inclusions with dilation and expansion of the ER and recent studies of iPS-derived hepatocyte-like cells from individuals with ATD indicate that the changes in the ER directly vary with the hepatic phenotype i.e there is much lesser alteration in the ER in cells derived from homozygotes that do not have clinically significant liver disease. From a signaling perspective, studies in mammalian cell line and animal models expressing the classical α1-antitrypsin Z variant (ATZ) have found that ER signaling is perturbed in a relatively unique way with powerful activation of autophagy and the NFκB pathway but relatively limited, if any, UPR signaling. It is still not known how much these unique structural and functional changes and the variation among affected homozygotes relate to the tendency of this variant to polymerize and aggregate and/ or to the repertoire of proteostasis mechanisms that are activated.

About this journal

The journal is closed for submissions.

Cell Pathology was a new title re-launched in 2020 in place of Endoplasmic Reticulum Stress in Diseases journal.

Cell Pathology was an open-access, peer-reviewed journal that focused on the abnormal state of cells driven by cell-intrinsic or extrinsic influences that manifest in changes of the morphology, loss of homeostasis, and/or alternations in the genetic profiles of cells. The journal welcomed anatomical, cellular, molecular, computational, mechanobiological, or organismal investigations of cell pathology and how abnormalities in cells portend to the initiation, development, and progression of human diseases.

Our journal sought high-quality original research reports, reviews, and commentaries related to all aspects of cell pathology. The editors considered basic, translational, and clinical investigations that describe novel anatomical discoveries, directly address mechanisms of pathogenesis, or provide a foundation for future cellular or molecular inquiries to aberrant physiology of cells. Examples of such foundational investigations encompass anatomical and molecular diagnostics, genomic classifications of diseases, mechanistic interrogations, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence were also welcomed. High priority was given to comprehensive studies that would advance our understandings of human cell pathology and disease.

The journal is archived by De Gruyter and the independent archiving service Portico.

All authors retain copyright, unless — due to their local circumstances — their work is not copyrighted. The copyrights are governed by the Creative-Commons license.