title: Endoplasmic reticulum membrane reorganization is regulated by ionic homeostasis.
abstract: Recently we described a new, evolutionarily conserved cellular stress response characterized by a reversible reorganization of endoplasmic reticulum (ER) membranes that is distinct from canonical ER stress and the unfolded protein response (UPR). Apogossypol, a putative broad spectrum BCL-2 family antagonist, was the prototype compound used to induce this ER membrane reorganization. Following microarray analysis of cells treated with apogossypol, we used connectivity mapping to identify a wide range of structurally diverse chemicals from different pharmacological classes and established their ability to induce ER membrane reorganization. Such structural diversity suggests that the mechanisms initiating ER membrane reorganization are also diverse and a major objective of the present study was to identify potentially common features of these mechanisms. In order to explore this, we used hierarchical clustering of transcription profiles for a number of chemicals that induce membrane reorganization and discovered two distinct clusters. One cluster contained chemicals with known effects on Ca(2+) homeostasis. Support for this was provided by the findings that ER membrane reorganization was induced by agents that either deplete ER Ca(2+) (thapsigargin) or cause an alteration in cellular Ca(2+) handling (calmodulin antagonists). Furthermore, overexpression of the ER luminal Ca(2+) sensor, STIM1, also evoked ER membrane reorganization. Although perturbation of Ca(2+) homeostasis was clearly one mechanism by which some agents induced ER membrane reorganization, influx of extracellular Na(+) but not Ca(2+) was required for ER membrane reorganization induced by apogossypol and the related BCL-2 family antagonist, TW37, in both human and yeast cells. Not only is this novel, non-canonical ER stress response evolutionary conserved but so also are aspects of the mechanism of formation of ER membrane aggregates. Thus perturbation of ionic homeostasis is important in the regulation of ER membrane reorganization.
authors: MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom.
authors: Shankar
authors: S
authors: Varadarajan
authors: Kayoko
authors: K
authors: Tanaka
authors: Joshua L
authors: JL
authors: Smalley
authors: Edward T W
authors: ET
authors: Bampton
authors: Maurizio
authors: M
authors: Pellecchia
authors: David
authors: D
authors: Dinsdale
authors: Gary B
authors: GB
authors: Willars
authors: Gerald M
authors: GM
authors: Cohen
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D016000:Cluster Analysis; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D012964:Sodium / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1
chemical_list: D002147:Calmodulin; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C492806:apogossypol; D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D006072:Gossypol; D002118:Calcium