%0 Journal Article
%T An Integrative Network Biology Approach to Evaluate the Role of Endoplasmic Reticulum Stress Response in Obese Type 2 Diabetes
%A Anup Mammen Oommen
%A Usha Narayanan
%A M. R. Jagannath
%J ISRN Cell Biology
%D 2012
%R 10.5402/2012/278636
%X Extracellular/intracellular stimuli can influence eukaryotic cell function through organelles that regulate critical signaling pathways. The endoplasmic reticulum (ER), for example, impacts cellular processes including protein synthesis, folding and secretion; amino acid transport; apoptosis; cell proliferation; lipid synthesis across major cell types in response to stimuli such as accumulation of misfolded proteins and glucose deprivation. Dysregulated signaling pathways underlying the ER-mediated processes mentioned above have been linked to disease conditions such as diabetes, obesity, and Alzheimer's disease. Our current understanding, however, lacks a detailed network view that integrates organelle-mediated pathway dysregulation with cellular processes and disease pathogenesis. In this report, we introduce an integrative network biology approach that combines ER-stress response pathways with basic cellular processes using data from peer-reviewed literature. As an example, we apply our systems biology approach to study the role of ER stress in pancreatic ¦Â cells under obese diabetic conditions, generate testable hypotheses, and provide novel insights into ¦Â-cell pathogenesis. 1. Introduction The endoplasmic reticulum (ER) is a 3D network of tubules and cisternae divided into the nuclear envelope, rough ER, and smooth ER, each with a distinct function. The ER performs numerous cellular functions including synthesis of secreted and membrane proteins, biosynthesis of phospholipids, cholesterol, and steroids, and degradation of glycogen and calcium homeostasis. Factors such as oxidative stress, ischemia, and increased load of nascent or misfolded proteins or perturbations in calcium homeostasis can interfere with normal ER function leading to an accumulation of misfolded proteins [1]. This process is called ¡°ER stress¡± and activates the unfolding protein response (UPR), which (a) helps restore normal cellular function by stopping protein translation, and (b) activates signaling pathways to increase production of molecular chaperones involved in protein folding [2]. If the disruption is prolonged, the UPR tries to turn on the apoptotic pathway [2]. Thus, the UPR safeguards protein synthesis, posttranslational modifications, folding and secretion, calcium storage and signaling, and lipid biosynthesis. Stresses that trigger UPR include elevated secretory protein synthesis; overexpression and/or accumulation of mutant proteins [3]; aberrant Ca2+ regulation [4]; hypoxia [5]; altered glycosylation [6]; ischemia [7]; viral infections [8]; redox state of ER
%U http://www.hindawi.com/journals/isrn.cell.biology/2012/278636/